Is AFAP1L2 p.Glu355Lys (c.1063G>A) pathogenic?

AFAP1L2 p.Glu355Lys (c.1063G>A) is classified Uncertain significance in AFAP1L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: ambiguous (0.4426); Rare (popmax 0.132%, mid).

How common is AFAP1L2 p.Glu355Lys (c.1063G>A) in the general population?

AFAP1L2 p.Glu355Lys (c.1063G>A) is rare (popmax 0.132%, mid) (gnomAD).

What do computational predictors say about AFAP1L2 p.Glu355Lys (c.1063G>A)?

AlphaMissense predicts ambiguous (score 0.4426) — an in-silico prediction, not a clinical call.

AFAP1L2 p.Glu355Lys

c.1063G>A · rs887113324 · VCV2371928

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4426 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.132%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4426	ambiguous
REVEL	0.194	benign-leaning
SaProt	LLR -6.75	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 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 100 kb · p 3.6e-05 · regional, not allelic
Overall
CADD	27.6	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 0.132% Middle Eastern · 8/6,072 alleles

Filtering AF 0.0655% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00372% 60/1,613,764 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.132%	759
African / African-American	0.0174%	5,759
Remaining individualsnot grpmax-eligible	0.016%	6,248
Admixed American	0.00667%	14,997
East Asian	0.00223%	44,866
South Asian	0.0022%	45,532
European (non-Finnish)	0.00178%	56,185
Finnishnot grpmax-eligible	0.00156%	64,032

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.Glu355Lys
Coding: c.1063G>A
MANE Select: NM_001001936
dbSNP: rs887113324
Type: single nucleotide variant
Location: chr10:114307814 (GRCh38)
Gene constraint: LOEUF 0.605 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.56 · 1 PDB
Residue 355: the ph 2 domain

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-glu355lys (accessed [today's date]).

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