Is ABCA7 p.Arg516Pro (c.1547G>C) pathogenic?

ABCA7 p.Arg516Pro (c.1547G>C) is classified Uncertain significance in ABCA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-17). AlphaMissense: ambiguous (0.4685); Ultra-rare (popmax 0.0902%, sas).

How common is ABCA7 p.Arg516Pro (c.1547G>C) in the general population?

ABCA7 p.Arg516Pro (c.1547G>C) is ultra-rare (popmax 0.0902%, sas) (gnomAD).

What do computational predictors say about ABCA7 p.Arg516Pro (c.1547G>C)?

AlphaMissense predicts ambiguous (score 0.4685) — an in-silico prediction, not a clinical call.

ABCA7 p.Arg516Pro

c.1547G>C · rs377020137 · VCV2347864

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0902%, sas)

Computational evidence

Protein change
AlphaMissense	0.4685	ambiguous
REVEL	0.622	indeterminate
SaProt	LLR -13.44	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.44	GERP 0.18
Regional constraint	o/e 1.14	unconstrained · MANE · 24 kb · p 5.6e-14 · regional, not allelic
Overall
CADD	21.0	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 0.0902% South Asian · 82/90,882 alleles

Filtering AF 0.0744% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0686%

Overall 0.0083% 133/1,602,508 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0902%	1,108
East Asian	0.0491%	2,037
Remaining individualsnot grpmax-eligible	0.0385%	2,598
Admixed American	0.0067%	14,930
European (non-Finnish)	8.48e-05%	1,178,780

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.Arg516Pro
Coding: c.1547G>C
MANE Select: NM_019112
dbSNP: rs377020137
Type: single nucleotide variant
Location: chr19:1046331 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.77 · 6 PDB
Residue 516: 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
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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-arg516pro (accessed [today's date]).

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