Is LCA5 p.Phe657Ser (c.1970T>C) pathogenic?

LCA5 p.Phe657Ser (c.1970T>C) is classified Uncertain significance in LCA5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-09-26). AlphaMissense: likely benign (0.1287); Very rare (popmax 8.48e-05%, nfe); Associated with Leber congenital amaurosis 5.

What condition is associated with LCA5 p.Phe657Ser (c.1970T>C)?

LCA5 p.Phe657Ser (c.1970T>C) is associated with Leber congenital amaurosis 5 (ClinVar).

How common is LCA5 p.Phe657Ser (c.1970T>C) in the general population?

LCA5 p.Phe657Ser (c.1970T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Leber congenital amaurosis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about LCA5 p.Phe657Ser (c.1970T>C)?

AlphaMissense predicts likely benign (score 0.1287) — an in-silico prediction, not a clinical call.

LCA5 p.Phe657Ser

c.1970T>C · rs1769683386 · VCV911363

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1287 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leber congenital amaurosis 5

Computational evidence

Protein change
AlphaMissense	0.1287	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -5.25	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 4.1	GERP 0.55, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 32 kb · p 0.58 · regional, not allelic
Overall
CADD	15.51	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,612 alleles

Overall 6.2e-05% 1/1,613,562 alleles · very rare exomes 1/1,461,472 · genomes 0/152,090 · joint denominator

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: LCA5
Protein: p.Phe657Ser
Coding: c.1970T>C
MANE Select: NM_001122769
dbSNP: rs1769683386
Type: single nucleotide variant
Location: chr6:79487128 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.05
Residue 657: the 'disordered' region

Full LCA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Leber congenital amaurosis 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

LCA5 c.190+1G>A Pathogenic/Likely pathogenic ★★ same condition
LCA5 c.721-1G>A Pathogenic/Likely pathogenic ★★ same condition
LCA5 c.721-2A>T Pathogenic/Likely pathogenic ★★ same condition
LCA5 c.858+1G>C Likely pathogenic ★★ same condition
LCA5 p.Ala319Thr Pathogenic/Likely pathogenic ★★ ⚠ same condition
LCA5 p.Arg218Ter Pathogenic/Likely pathogenic ★★ same condition
LCA5 p.Arg255Ter Pathogenic ★★ same condition
LCA5 p.Arg280Ter 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/lca5-p-phe657ser (accessed [today's date]).

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