Is AIPL1 p.Ala313Ser (c.937G>T) pathogenic?

AIPL1 p.Ala313Ser (c.937G>T) is classified Benign in AIPL1 (ClinVar, Expert panel, 8 submitters; last evaluated 2025-09-29). AlphaMissense: likely benign (0.118); Low-frequency (popmax 1.66%, afr); Associated with AIPL1-related retinopathy.

What condition is associated with AIPL1 p.Ala313Ser (c.937G>T)?

AIPL1 p.Ala313Ser (c.937G>T) is associated with AIPL1-related retinopathy, Leber congenital amaurosis 4 (ClinVar).

How common is AIPL1 p.Ala313Ser (c.937G>T) in the general population?

AIPL1 p.Ala313Ser (c.937G>T) is low-frequency (popmax 1.66%, afr) (gnomAD).

What do computational predictors say about AIPL1 p.Ala313Ser (c.937G>T)?

AlphaMissense predicts likely benign (score 0.118) — an in-silico prediction, not a clinical call.

AIPL1 p.Ala313Ser

c.937G>T · rs115681466 · VCV100585

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.118 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.66%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AIPL1-related retinopathy

ClinGen expert panel — Leber Congenital Amaurosis/early onset Retinal Dystrophy VCEP

Benign for AIPL1-related retinopathy. Applied ACMG criteria (verbatim):

BS2 BP4_Moderate BA1

Curation rationale (ClinGen, verbatim)

NM_014336.5(AIPL1):c.937G>T (p.Ala313Ser) is a missense variant in exon 6 of 6. The variant is predicted to change the amino acid alanine at position p.313 to serine. This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.01581, with 1,244 alleles / 75,040 total alleles in the African/African American population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.0057 (BA1). The variant has been found in the homozygous state in 16 adult individuals in gnomAD which exceeds the LCA/eoRD VCEP threshold of ≥6 (gnomAD version 4.1.0; BS2). The computational predictor REVEL gives a score of 0.069, which is below the ClinGen LCA/eoRD VCEP threshold of ≤0.183 and predicts a non-damaging effect on AIPL1 protein function. In addition, the phyloP score is 1.28882 (suggesting low conservation) and the splicing impact predictor SpliceAI gives a delta score of 0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for AIPL1-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS2, and BP4_Moderate. (VCEP specifications version 1.0.0; date of approval 09/24/2025).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.118	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -7.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -1.2, phastCons 0.94
Regional constraint	o/e 0.96	unconstrained · MANE · 9,641 bp · p 0.35 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.66% African / African-American · 1,244/75,040 alleles

Filtering AF 1.58% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.55%

Overall 0.114% 1,841/1,610,000 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.66%	60
Middle Eastern	0.264%	379
Remaining individualsnot grpmax-eligible	0.179%	558
Admixed American	0.163%	612
European (non-Finnish)	0.0307%	3,260
South Asian	0.00769%	13,011
East Asian	0.00223%	44,878
Finnishnot grpmax-eligible	0.00167%	59,984

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AIPL1
Protein: p.Ala313Ser
Coding: c.937G>T
MANE Select: NM_014336
dbSNP: rs115681466
Type: single nucleotide variant
Location: chr17:6425678 (GRCh38)
Gene constraint: LOEUF 1.01 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.42 · 6 PDB

Full AIPL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: Leber congenital amaurosis 4

Similar variants

AIPL1 p.Ala313Thr Uncertain significance ★ ⚠ same residue
AIPL1 p.Ala313Val Uncertain significance ★ ⚠ same residue
AIPL1 p.Ala313= Likely benign ★ same residue
AIPL1 c.276+1G>A Pathogenic ★★★ same condition
AIPL1 c.276+2T>C Pathogenic ★★★ same condition
AIPL1 c.277-2A>G Pathogenic ★★★ same condition
AIPL1 p.Ala197Pro Pathogenic ★★★ same condition
AIPL1 p.Arg270His Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/aipl1-p-ala313ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown