Is ABCA6 p.Pro146Ser (c.436C>T) pathogenic?

ABCA6 p.Pro146Ser (c.436C>T) is classified Uncertain significance in ABCA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-14). AlphaMissense: likely benign (0.1711); Rare (popmax 0.105%, afr).

How common is ABCA6 p.Pro146Ser (c.436C>T) in the general population?

ABCA6 p.Pro146Ser (c.436C>T) is rare (popmax 0.105%, afr) (gnomAD).

What do computational predictors say about ABCA6 p.Pro146Ser (c.436C>T)?

AlphaMissense predicts likely benign (score 0.1711) — an in-silico prediction, not a clinical call.

ABCA6 p.Pro146Ser

c.436C>T · rs140469761 · VCV2239794

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1711 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1711	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -4.39	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 62 kb · p 0.14 · regional, not allelic
Overall
CADD	20.7	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 0.105% African / African-American · 79/74,984 alleles

Filtering AF 0.0866% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0797%

Overall 0.00534% 86/1,610,300 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.105%	949
Admixed American	0.00167%	59,738
Remaining individualsnot grpmax-eligible	0.0016%	62,314
European (non-Finnish)	0.000424%	235,576

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.Pro146Ser
Coding: c.436C>T
MANE Select: NM_080284
dbSNP: rs140469761
Type: single nucleotide variant
Location: chr17:69136116 (GRCh38)
Gene constraint: LOEUF 1.041 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.38

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

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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-pro146ser (accessed [today's date]).

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