Is AFAP1 p.Ser763Leu (c.2288C>T) pathogenic?

AFAP1 p.Ser763Leu (c.2288C>T) is classified Uncertain significance in AFAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely benign (0.1022); Ultra-rare (popmax 0.0293%, afr).

How common is AFAP1 p.Ser763Leu (c.2288C>T) in the general population?

AFAP1 p.Ser763Leu (c.2288C>T) is ultra-rare (popmax 0.0293%, afr) (gnomAD).

What do computational predictors say about AFAP1 p.Ser763Leu (c.2288C>T)?

AlphaMissense predicts likely benign (score 0.1022) — an in-silico prediction, not a clinical call.

AFAP1 p.Ser763Leu

c.2288C>T · VCV4246868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1022 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0293%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1022	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -8.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 108 kb · p 3.6e-06 · regional, not allelic
Overall
CADD	30.0	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S679L vs ClinVar S763L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0293% African / African-American · 22/75,048 alleles

Filtering AF 0.0198% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00229% 37/1,613,610 alleles · ultra-rare exomes 22/1,461,284 · genomes 15/152,326 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0293%	3,411
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.0033%	30,341
East Asian	0.00223%	44,868
Remaining individualsnot grpmax-eligible	0.0016%	62,496
European (non-Finnish)	0.000763%	131,069

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.Ser763Leu
Coding: c.2288C>T
MANE Select: NM_001134647
Type: single nucleotide variant
Location: chr4:7768974 (GRCh38)

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

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-ser763leu (accessed [today's date]).

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