Is AFAP1 p.Ala438Ser (c.1312G>T) pathogenic?

AFAP1 p.Ala438Ser (c.1312G>T) is classified Uncertain significance in AFAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-18). AlphaMissense: likely benign (0.1009); Ultra-rare (popmax 0.0508%, mid).

How common is AFAP1 p.Ala438Ser (c.1312G>T) in the general population?

AFAP1 p.Ala438Ser (c.1312G>T) is ultra-rare (popmax 0.0508%, mid) (gnomAD).

What do computational predictors say about AFAP1 p.Ala438Ser (c.1312G>T)?

AlphaMissense predicts likely benign (score 0.1009) — an in-silico prediction, not a clinical call.

AFAP1 p.Ala438Ser

c.1312G>T · rs759438734 · VCV3091606

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1009 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0508%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1009	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -6.03	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 5.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 108 kb · p 3.6e-06 · regional, not allelic
Overall
CADD	21.7	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 0.0508% Middle Eastern · 3/5,904 alleles

Filtering AF 0.0138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00737%

Overall 0.00371% 58/1,564,366 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0508%	1,968
Remaining individualsnot grpmax-eligible	0.00668%	14,966
European (non-Finnish)	0.00438%	22,842
East Asian	0.00228%	43,914

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.Ala438Ser
Coding: c.1312G>T
MANE Select: NM_001134647
dbSNP: rs759438734
Type: single nucleotide variant
Location: chr4:7793781 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.09
Residue 438: 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.Ala534Ser Uncertain significance ★ same type
AFAP1 p.Ala587Val Uncertain significance ★ same type
AFAP1 p.Ala624Val Uncertain significance ★ ⚠ same type
AFAP1 p.Ala682Thr 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-ala438ser (accessed [today's date]).

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