Is ABCA7 p.Arg463His (c.1388G>A) pathogenic?

ABCA7 p.Arg463His (c.1388G>A) is classified Benign in ABCA7 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-08-22). AlphaMissense: likely benign (0.1015); Common (popmax 16.3%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ABCA7 p.Arg463His (c.1388G>A)?

AlphaMissense predicts likely benign (score 0.1015) — an in-silico prediction, not a clinical call.

ABCA7 p.Arg463His

Q: How common is ABCA7 p.Arg463His (c.1388G>A) in the general population?

ABCA7 p.Arg463His (c.1388G>A) is common (popmax 16.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1388G>A · rs3752233 · VCV1249491

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1015 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 16.3%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1015	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -8.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.34	GERP -3.3
Regional constraint	o/e 1.14	unconstrained · MANE · 24 kb · p 5.6e-14 · regional, not allelic
Overall
CADD	19.11	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 16.3% East Asian · 7,317/44,840 alleles

Filtering AF 16% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.9%

Overall 4.22% 67,936/1,610,838 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	16.3%	6
Finnishnot grpmax-eligible	5.72%	17
South Asian	5.17%	19
Remaining individualsnot grpmax-eligible	4.48%	22
European (non-Finnish)	4.01%	25
Ashkenazi Jewishnot grpmax-eligible	2.84%	35
Admixed American	1.45%	69
Middle Eastern	0.99%	101
Amishnot grpmax-eligible	0.661%	151
African / African-American	0.648%	154

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.Arg463His
Coding: c.1388G>A
MANE Select: NM_019112
dbSNP: rs3752233
Type: single nucleotide variant
Location: chr19:1045174 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.77 · 6 PDB
Residue 463: a UniProt-annotated variant site (in); a β-strand

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

Similar variants

ABCA7 c.2684+5G>A Uncertain significance ★★ same type
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ABCA7 p.Arg1026Cys Uncertain significance ★★ ⚠ same type
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
ABCA7 p.Gln925Ter Uncertain significance ★★ 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/abca7-p-arg463his (accessed [today's date]).

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