Is WAPL p.Arg900His (c.2699G>A) pathogenic?

WAPL p.Arg900His (c.2699G>A) is classified Uncertain significance in WAPL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely benign (0.2109); Very rare (popmax 0.00267%, afr).

How common is WAPL p.Arg900His (c.2699G>A) in the general population?

WAPL p.Arg900His (c.2699G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about WAPL p.Arg900His (c.2699G>A)?

AlphaMissense predicts likely benign (score 0.2109) — an in-silico prediction, not a clinical call.

WAPL p.Arg900His

c.2699G>A · rs1469974411 · VCV2355118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2109 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2109	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -5.91	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 1,723 bp · p 2.7e-05 · regional, not allelic
Overall
CADD	28.6	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 0.00267% African / African-American · 2/74,860 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000806% 13/1,613,226 alleles · very rare exomes 11/1,461,068 · genomes 2/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,430
Admixed American	0.00167%	59,752
South Asian	0.0011%	90,792
European (non-Finnish)	0.000763%	131,099

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: WAPL
Protein: p.Arg900His
Coding: c.2699G>A
MANE Select: NM_015045
dbSNP: rs1469974411
Type: single nucleotide variant
Location: chr10:86453790 (GRCh38)
Gene constraint: LOEUF 0.083 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.26 · 3 PDB
Residue 900: the wapl domain

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

Similar variants

WAPL c.2949+1G>T Uncertain significance ★ same type
WAPL p.Ala1032Thr Uncertain significance ★ ⚠ same type
WAPL p.Ala278Thr Uncertain significance ★ ⚠ same type
WAPL p.Ala337Thr Uncertain significance ★ ⚠ same type
WAPL p.Arg1043Ter Uncertain significance ★ same type
WAPL p.Arg1045Trp Uncertain significance ★ ⚠ same type
WAPL p.Arg247Thr Uncertain significance ★ ⚠ same type
WAPL p.Arg379His 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/wapl-p-arg900his (accessed [today's date]).

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