Is WIPF1 p.Pro399Arg (c.1196C>G) pathogenic?

WIPF1 p.Pro399Arg (c.1196C>G) is classified Uncertain significance in WIPF1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-23). AlphaMissense: likely pathogenic (0.6412); Ultra-rare (popmax 0.0223%, eas); Associated with Wiskott-Aldrich syndrome 2.

What condition is associated with WIPF1 p.Pro399Arg (c.1196C>G)?

WIPF1 p.Pro399Arg (c.1196C>G) is associated with Wiskott-Aldrich syndrome 2 (ClinVar).

How common is WIPF1 p.Pro399Arg (c.1196C>G) in the general population?

WIPF1 p.Pro399Arg (c.1196C>G) is ultra-rare (popmax 0.0223%, eas) (gnomAD).

What do computational predictors say about WIPF1 p.Pro399Arg (c.1196C>G)?

AlphaMissense predicts likely pathogenic (score 0.6412) — an in-silico prediction, not a clinical call.

WIPF1 p.Pro399Arg

c.1196C>G · rs1684716723 · VCV1431031

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6412 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Wiskott-Aldrich syndrome 2

Computational evidence

Protein change
AlphaMissense	0.6412	likely pathogenic
REVEL	0.602	indeterminate
SaProt	LLR -11.89	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 5,488 bp · p 0.0077 · regional, not allelic
Overall
CADD	28.8	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 0.0223% East Asian · 10/44,882 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00916%

Overall 0.00157% 23/1,461,690 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,488
Admixed American	0.00167%	60,022
European (non-Finnish)	0.00102%	98,335

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: WIPF1
Protein: p.Pro399Arg
Coding: c.1196C>G
MANE Select: NM_001375834
dbSNP: rs1684716723
Type: single nucleotide variant
Location: chr2:174568007 (GRCh38)
Gene constraint: LOEUF 0.565 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 59.19 · 5 PDB
Residue 399: the 'disordered' region

Full WIPF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Wiskott-Aldrich syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

WIPF1 p.Pro399Leu Uncertain significance ★ ⚠ same residue
WIPF1 p.Ala259Val Uncertain significance ★★ ⚠ same condition
WIPF1 p.Ala281Pro Uncertain significance ★★ ⚠ same condition
WIPF1 p.Arg125Gln Uncertain significance ★★ ⚠ same condition
WIPF1 p.Arg201Trp Uncertain significance ★★ ⚠ same condition
WIPF1 p.Arg393Trp Uncertain significance ★★ ⚠ same condition
WIPF1 p.Arg485Gln Uncertain significance ★★ ⚠ same condition
WIPF1 p.Arg485Trp Uncertain significance ★★ ⚠ same condition

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/wipf1-p-pro399arg (accessed [today's date]).

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