Is ABCA7 p.Arg334Trp (c.1000C>T) pathogenic?

ABCA7 p.Arg334Trp (c.1000C>T) is classified Uncertain significance in ABCA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-10). AlphaMissense: likely benign (0.1181); Ultra-rare (popmax 0.0337%, nfe).

How common is ABCA7 p.Arg334Trp (c.1000C>T) in the general population?

ABCA7 p.Arg334Trp (c.1000C>T) is ultra-rare (popmax 0.0337%, nfe) (gnomAD).

What do computational predictors say about ABCA7 p.Arg334Trp (c.1000C>T)?

AlphaMissense predicts likely benign (score 0.1181) — an in-silico prediction, not a clinical call.

ABCA7 p.Arg334Trp

c.1000C>T · rs146086314 · VCV2222998

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1181 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0337%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1181	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -9.37	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 1.3	GERP -1, phastCons 0.001
Regional constraint	o/e 1.14	unconstrained · MANE · 24 kb · p 5.6e-14 · regional, not allelic
Overall
CADD	23.9	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 0.0337% European (non-Finnish) · 398/1,179,744 alleles

Filtering AF 0.031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.0278% 448/1,612,386 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0337%	2,964
African / African-American	0.0295%	3,392
Admixed American	0.0217%	4,608
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0144%	6,942
Finnishnot grpmax-eligible	0.00791%	12,648

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.Arg334Trp
Coding: c.1000C>T
MANE Select: NM_019112
dbSNP: rs146086314
Type: single nucleotide variant
Location: chr19:1043794 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.77 · 6 PDB
Residue 334: an α-helix

Full ABCA7 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/abca7-p-arg334trp (accessed [today's date]).

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