Is ABCA7 p.Ala657Val (c.1970C>T) pathogenic?

ABCA7 p.Ala657Val (c.1970C>T) is classified Uncertain significance in ABCA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-19). AlphaMissense: ambiguous (0.3705); Very rare (popmax 0.00585%, nfe).

How common is ABCA7 p.Ala657Val (c.1970C>T) in the general population?

ABCA7 p.Ala657Val (c.1970C>T) is very rare (popmax 0.00585%, nfe) (gnomAD).

What do computational predictors say about ABCA7 p.Ala657Val (c.1970C>T)?

AlphaMissense predicts ambiguous (score 0.3705) — an in-silico prediction, not a clinical call.

ABCA7 p.Ala657Val

c.1970C>T · rs141937680 · VCV3109567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3705 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00585%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3705	ambiguous
REVEL	0.608	indeterminate
SaProt	LLR -13.49	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.9, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 24 kb · p 5.6e-14 · regional, not allelic
Overall
CADD	25.4	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 0.00585% European (non-Finnish) · 69/1,178,820 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.00461% 74/1,604,474 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00585%	17,084
Remaining individualsnot grpmax-eligible	0.00482%	20,740
Finnishnot grpmax-eligible	0.00176%	56,820
South Asian	0.0011%	90,724

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: ABCA7
Protein: p.Ala657Val
Coding: c.1970C>T
MANE Select: NM_019112
dbSNP: rs141937680
Type: single nucleotide variant
Location: chr19:1047281 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.77 · 6 PDB
Residue 657: an α-helix

Full ABCA7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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ABCA7 p.Arg652Cys Uncertain significance ★★ ⚠ same type
ABCA7 p.Arg880Trp Uncertain significance ★★ ⚠ same type
ABCA7 p.Asp1452Asn Uncertain significance ★★ ⚠ same type
ABCA7 p.Asp2085Asn 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/abca7-p-ala657val (accessed [today's date]).

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