Is ABCA5 p.Ser469Ala (c.1405T>G) pathogenic?

ABCA5 p.Ser469Ala (c.1405T>G) is classified Benign in ABCA5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0693); Common (popmax 5.78%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ABCA5 p.Ser469Ala (c.1405T>G)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

ABCA5 p.Ser469Ala

Q: How common is ABCA5 p.Ser469Ala (c.1405T>G) in the general population?

ABCA5 p.Ser469Ala (c.1405T>G) is common (popmax 5.78%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1405T>G · rs114790500 · VCV777718

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.78%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -6.41	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 9.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 67 kb · p 0.22 · regional, not allelic
Overall
CADD	23.8	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 5.78% African / African-American · 4,329/74,854 alleles

Filtering AF 5.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.58%

Overall 0.315% 5,082/1,611,624 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.78%	17
Admixed American	0.487%	205
Remaining individualsnot grpmax-eligible	0.445%	225
Middle Eastern	0.314%	319
European (non-Finnish)	0.0133%	7,512
South Asian	0.00999%	10,010

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: ABCA5
Protein: p.Ser469Ala
Coding: c.1405T>G
MANE Select: NM_172232
dbSNP: rs114790500
Type: single nucleotide variant
Location: chr17:69297222 (GRCh38)
Gene constraint: LOEUF 0.97 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.12

Full ABCA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCA5 p.Ser288Phe Uncertain significance ★★ ⚠ same type
ABCA5 c.4765+3A>G Likely benign ★★ same type
ABCA5 p.Asn190Ser Likely benign ★★ ⚠ same type
ABCA5 p.Asn768Asp Benign ★★ same type
ABCA5 p.Asp817Tyr Likely benign ★★ ⚠ same type
ABCA5 p.Gly1159Arg Likely benign ★★ ⚠ same type
ABCA5 p.Gly128= Benign/Likely benign ★★ same type
ABCA5 p.Ile1173Val Likely benign ★★ same type

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/abca5-p-ser469ala (accessed [today's date]).

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