Is AFAP1L1 p.Arg396His (c.1187G>A) pathogenic?

AFAP1L1 p.Arg396His (c.1187G>A) is classified Uncertain significance in AFAP1L1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-08). AlphaMissense: likely benign (0.2138); Ultra-rare (popmax 0.032%, afr).

How common is AFAP1L1 p.Arg396His (c.1187G>A) in the general population?

AFAP1L1 p.Arg396His (c.1187G>A) is ultra-rare (popmax 0.032%, afr) (gnomAD).

What do computational predictors say about AFAP1L1 p.Arg396His (c.1187G>A)?

AlphaMissense predicts likely benign (score 0.2138) — an in-silico prediction, not a clinical call.

AFAP1L1 p.Arg396His

c.1187G>A · rs369601847 · VCV2599505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2138 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.032%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2138	likely benign
REVEL	0.657	pathogenic-leaning
SaProt	LLR -7.30	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 68 kb · p 0.001 · regional, not allelic
Overall
CADD	29.9	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 0.032% African / African-American · 24/74,900 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0187%

Overall 0.00285% 46/1,613,976 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.032%	3,121
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Admixed American	0.00333%	29,998
East Asian	0.00223%	44,884
European (non-Finnish)	0.00127%	78,668

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: AFAP1L1
Protein: p.Arg396His
Coding: c.1187G>A
MANE Select: NM_152406
dbSNP: rs369601847
Type: single nucleotide variant
Location: chr5:149316223 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.40

Full AFAP1L1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFAP1L1 p.Ala110Val Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala130Gly Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala184Thr Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala582Thr Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala615Val Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala670Ser Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala674Val Uncertain significance ★ ⚠ same type
AFAP1L1 p.Ala721Thr 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/afap1l1-p-arg396his (accessed [today's date]).

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