Is AFAP1L2 p.Ala6Val (c.17C>T) pathogenic?

AFAP1L2 p.Ala6Val (c.17C>T) is classified Uncertain significance in AFAP1L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: ambiguous (0.4069); Ultra-rare (popmax 0.0165%, mid).

How common is AFAP1L2 p.Ala6Val (c.17C>T) in the general population?

AFAP1L2 p.Ala6Val (c.17C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about AFAP1L2 p.Ala6Val (c.17C>T)?

AlphaMissense predicts ambiguous (score 0.4069) — an in-silico prediction, not a clinical call.

AFAP1L2 p.Ala6Val

c.17C>T · VCV4638735

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4069 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4069	ambiguous
REVEL	0.038	moderately benign-leaning
SaProt	LLR -3.96	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.68, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 100 kb · p 3.6e-05 · regional, not allelic
Overall
CADD	23.2	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000494%

Overall 0.000248% 4/1,614,194 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.004%	25,018

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: AFAP1L2
Protein: p.Ala6Val
Coding: c.17C>T
MANE Select: NM_001001936
Type: single nucleotide variant
Location: chr10:114340731 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.56 · 1 PDB

Full AFAP1L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFAP1L2 p.Arg648His Uncertain significance ★★ ⚠ same type
AFAP1L2 p.Arg730= Benign/Likely benign ★★ same type
VWA2 p.Arg682Trp Benign ★★ ⚠ same type
VWA2 p.Asn331= Benign ★★ same type
VWA2 p.Gly641= Likely benign ★★ same type
VWA2 p.His496Tyr Benign ★★ same type
VWA2 p.Phe365= Benign ★★ same type
VWA2 p.Pro544= Benign ★★ 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/afap1l2-p-ala6val (accessed [today's date]).

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