Is AFAP1 p.Arg365His (c.1094G>A) pathogenic?

AFAP1 p.Arg365His (c.1094G>A) is classified Uncertain significance in AFAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: likely benign (0.3321); Ultra-rare (popmax 0.033%, mid).

How common is AFAP1 p.Arg365His (c.1094G>A) in the general population?

AFAP1 p.Arg365His (c.1094G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about AFAP1 p.Arg365His (c.1094G>A)?

AlphaMissense predicts likely benign (score 0.3321) — an in-silico prediction, not a clinical call.

AFAP1 p.Arg365His

c.1094G>A · rs1188346316 · VCV2331374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3321 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3321	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -8.38	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 7.4	GERP 2.6, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 108 kb · p 3.6e-06 · regional, not allelic
Overall
CADD	32.0	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00335% 49/1,461,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.008%	12,502
European (non-Finnish)	0.00339%	29,501
South Asian	0.0022%	45,537

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: AFAP1
Protein: p.Arg365His
Coding: c.1094G>A
MANE Select: NM_001134647
dbSNP: rs1188346316
Type: single nucleotide variant
Location: chr4:7800614 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.09
Residue 365: the ph 2 domain

Full AFAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFAP1 p.Val288Ala Uncertain significance ★★ ⚠ same type
AFAP1 p.Ala783= Likely benign ★★ same type
AFAP1 p.Asn686= Likely benign ★★ same type
AFAP1 p.Glu705= Benign ★★ same type
AFAP1 p.Ala438Ser Uncertain significance ★ ⚠ same type
AFAP1 p.Ala534Ser Uncertain significance ★ same type
AFAP1 p.Ala587Val Uncertain significance ★ same type
AFAP1 p.Ala624Val 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/afap1-p-arg365his (accessed [today's date]).

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