Is AFAP1 p.Pro335Leu (c.1004C>T) pathogenic?

AFAP1 p.Pro335Leu (c.1004C>T) is classified Uncertain significance in AFAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.202); Very rare (popmax 0.00356%, nfe).

How common is AFAP1 p.Pro335Leu (c.1004C>T) in the general population?

AFAP1 p.Pro335Leu (c.1004C>T) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about AFAP1 p.Pro335Leu (c.1004C>T)?

AlphaMissense predicts likely benign (score 0.202) — an in-silico prediction, not a clinical call.

AFAP1 p.Pro335Leu

c.1004C>T · VCV4246910

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.202 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.202	likely benign
REVEL	0.316	indeterminate
SaProt	LLR -7.49	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 108 kb · p 3.6e-06 · regional, not allelic
Overall
CADD	29.1	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 0.00356% European (non-Finnish) · 42/1,179,998 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00285% 46/1,613,916 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00356%	28,095
African / African-American	0.00267%	37,443
South Asian	0.0022%	45,531

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.Pro335Leu
Coding: c.1004C>T
MANE Select: NM_001134647
Type: single nucleotide variant
Location: chr4:7809664 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.09

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-pro335leu (accessed [today's date]).

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