Is AFAP1L2 p.Leu7Pro (c.20T>C) pathogenic?

AFAP1L2 p.Leu7Pro (c.20T>C) is classified Uncertain significance in AFAP1L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). AlphaMissense: likely pathogenic (0.9635); Very rare (popmax 0.00339%, nfe).

How common is AFAP1L2 p.Leu7Pro (c.20T>C) in the general population?

AFAP1L2 p.Leu7Pro (c.20T>C) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about AFAP1L2 p.Leu7Pro (c.20T>C)?

AlphaMissense predicts likely pathogenic (score 0.9635) — an in-silico prediction, not a clinical call.

AFAP1L2 p.Leu7Pro

c.20T>C · VCV3503553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9635	likely pathogenic · top 8% in AFAP1L2
REVEL	0.605	indeterminate
SaProt	LLR -11.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 100 kb · p 3.6e-05 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00339% European (non-Finnish) · 40/1,180,026 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00254% 41/1,614,076 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00339%	29,501
Admixed American	0.00167%	60,004

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.Leu7Pro
Coding: c.20T>C
MANE Select: NM_001001936
Type: single nucleotide variant
Location: chr10:114340728 (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-leu7pro (accessed [today's date]).

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