Is ABCA4 p.Ser2129Asn (c.6386G>A) pathogenic?

ABCA4 p.Ser2129Asn (c.6386G>A) is classified Likely pathogenic in ABCA4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.7593); Very rare (popmax 6.84e-05%); Associated with Stargardt disease.

What condition is associated with ABCA4 p.Ser2129Asn (c.6386G>A)?

ABCA4 p.Ser2129Asn (c.6386G>A) is associated with Stargardt disease, age related macular degeneration 2, cone-rod dystrophy (ClinVar).

How common is ABCA4 p.Ser2129Asn (c.6386G>A) in the general population?

ABCA4 p.Ser2129Asn (c.6386G>A) is very rare (popmax 6.84e-05%) (gnomAD).

How is Stargardt disease inherited?

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

What do computational predictors say about ABCA4 p.Ser2129Asn (c.6386G>A)?

AlphaMissense predicts likely pathogenic (score 0.7593) — an in-silico prediction, not a clinical call.

ABCA4 p.Ser2129Asn

c.6386G>A · rs1571242070 · VCV812194

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7593 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Stargardt disease

Computational evidence

Protein change
AlphaMissense	0.7593	likely pathogenic ✓ concordant with ClinVar
REVEL	0.621	indeterminate
SaProt	LLR -11.51	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.87	donor loss · deltas
Pangolin	Δ0.67	loss · gain 0.29 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	32.0	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 6.84e-05%

Overall 6.84e-05% 1/1,461,870 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.Ser2129Asn
Coding: c.6386G>A
MANE Select: NM_000350
dbSNP: rs1571242070
Type: single nucleotide variant
Location: chr1:94001002 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 2129: 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)

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

Disease context

Stargardt disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 2 cone-rod dystrophy

For Stargardt disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ABCA4 p.Ser2129Gly Likely pathogenic ★ same residue
ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
ABCA4 c.4352+1G>A Pathogenic ★★★ same condition
ABCA4 c.4773+3A>G Pathogenic ★★★ same condition
ABCA4 c.5196+1137G>A Pathogenic ★★★ same condition
ABCA4 c.5460+1G>A Pathogenic ★★★ same condition
ABCA4 c.5461-10T>C Pathogenic ★★★ same condition
ABCA4 c.5714+5G>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-ser2129asn (accessed [today's date]).

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