Is ABCA6 p.Ser1329Pro (c.3985T>C) pathogenic?

ABCA6 p.Ser1329Pro (c.3985T>C) is classified Uncertain significance in ABCA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). AlphaMissense: likely pathogenic (0.6202); Ultra-rare (popmax 0.0165%, mid).

How common is ABCA6 p.Ser1329Pro (c.3985T>C) in the general population?

ABCA6 p.Ser1329Pro (c.3985T>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ABCA6 p.Ser1329Pro (c.3985T>C)?

AlphaMissense predicts likely pathogenic (score 0.6202) — an in-silico prediction, not a clinical call.

ABCA6 p.Ser1329Pro

c.3985T>C · VCV3961626

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6202 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6202	likely pathogenic · top 8% in ABCA6
REVEL	0.58	indeterminate
SaProt	LLR -12.24	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.08	GERP -1.1
Regional constraint	o/e 1.03	unconstrained · MANE · 62 kb · p 0.14 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0165% Middle Eastern · 1/6,074 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00248% 40/1,612,546 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,074
Admixed American	0.00335%	29,859
European (non-Finnish)	0.00297%	33,694
Remaining individualsnot grpmax-eligible	0.0016%	62,444
South Asian	0.0011%	90,794

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: ABCA6
Protein: p.Ser1329Pro
Coding: c.3985T>C
MANE Select: NM_080284
Type: single nucleotide variant
Location: chr17:69085669 (GRCh38)
Gene constraint: LOEUF 1.041 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.38
Residue 1329: the abc transporter 2 domain

Full ABCA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ABCA6 p.Ala1303Thr Uncertain significance ★ ⚠ same type
ABCA6 p.Ala1389Glu Uncertain significance ★ ⚠ same type
ABCA6 p.Ala1392Thr Uncertain significance ★ ⚠ same type
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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/abca6-p-ser1329pro (accessed [today's date]).

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