Is ABCA4 p.Pro68Arg (c.203C>G) pathogenic?

ABCA4 p.Pro68Arg (c.203C>G) is classified Pathogenic/Likely pathogenic in ABCA4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-05-05). AlphaMissense: likely pathogenic (0.6781); Very rare (popmax 0.000508%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with ABCA4 p.Pro68Arg (c.203C>G)?

ABCA4 p.Pro68Arg (c.203C>G) is associated with inherited retinal dystrophy, cone-rod dystrophy 3 (ClinVar).

How common is ABCA4 p.Pro68Arg (c.203C>G) in the general population?

ABCA4 p.Pro68Arg (c.203C>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about ABCA4 p.Pro68Arg (c.203C>G)?

AlphaMissense predicts likely pathogenic (score 0.6781) — an in-silico prediction, not a clinical call.

ABCA4 p.Pro68Arg

c.203C>G · rs62654397 · VCV99112

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.6781	likely pathogenic ✓ concordant with ClinVar
REVEL	0.923	moderately pathogenic-leaning
SaProt	LLR -10.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	25.0	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 0.000508% European (non-Finnish) · 6/1,180,010 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00041% 6/1,461,852 alleles · very rare

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.Pro68Arg
Coding: c.203C>G
MANE Select: NM_000350
dbSNP: rs62654397
Type: single nucleotide variant
Location: chr1:94111537 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 68: an α-helix; a disulfide bond; a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1)

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

Disease context

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cone-rod dystrophy 3

Similar variants

ABCA4 p.Pro68Leu Pathogenic ★★★ ⚠ same residue
ABCA4 p.Pro68= Likely benign ★ same residue
ABCA4 c.1937+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
ABCA4 c.5018+2T>A 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-pro68arg (accessed [today's date]).

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