Is ABCA4 p.Val2114Met (c.6340G>A) pathogenic?

ABCA4 p.Val2114Met (c.6340G>A) is classified Likely benign in ABCA4 (ClinVar, Expert panel, 7 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.0781); Ultra-rare (popmax 0.0156%, eas); Associated with ABCA4-related retinopathy.

What condition is associated with ABCA4 p.Val2114Met (c.6340G>A)?

ABCA4 p.Val2114Met (c.6340G>A) is associated with ABCA4-related retinopathy, inherited retinal dystrophy (ClinVar).

How common is ABCA4 p.Val2114Met (c.6340G>A) in the general population?

ABCA4 p.Val2114Met (c.6340G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about ABCA4 p.Val2114Met (c.6340G>A)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

ABCA4 p.Val2114Met

c.6340G>A · rs202127235 · VCV298223

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related retinopathy

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.261	benign-leaning
SaProt	LLR -5.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -2.5	GERP -3.7
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	6.558	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 0.0156% East Asian · 7/44,864 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.0116% 187/1,614,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.324%	308
Remaining individualsnot grpmax-eligible	0.0272%	3,677
East Asiangrpmax	0.0156%	6,409
European (non-Finnish)	0.00534%	18,731
Admixed American	0.005%	20,009
South Asian	0.0011%	91,074

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ABCA4
Protein: p.Val2114Met
Coding: c.6340G>A
MANE Select: NM_000350
dbSNP: rs202127235
Type: single nucleotide variant
Location: chr1:94001048 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 2114: a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (found in a patient with chorioretinal atrophy; uncertain significance); a UniProt-annotated variant site (found in a patient with macular dystrophy; uncertain significance); the abc transporter 2 domain; a UniProt-annotated variant site (in stgd1 and cord3; uncertain significance); a UniProt-annotated variant site (sequence variant); a UniProt-annotated variant site (in stgd1 and ffm; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance; also found in a patient with chorioretinal atrophy; uncertain significance); an α-helix

Full ABCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: inherited retinal dystrophy

Similar variants

ABCA4 p.Val2114= Pathogenic/Likely pathogenic ★★ same residue
ABCA4 c.1937+1G>A Pathogenic ★★★ same condition
ABCA4 c.3328+2T>A Pathogenic ★★★ same condition
ABCA4 c.3523-1G>A Pathogenic ★★★ same condition
ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
ABCA4 c.4254-1G>C Pathogenic ★★★ same condition
ABCA4 c.4352+1G>A Pathogenic ★★★ same condition
ABCA4 c.4773+3A>G 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/abca4-p-val2114met (accessed [today's date]).

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