Is CWH43 p.Pro59Arg (c.176C>G) pathogenic?

CWH43 p.Pro59Arg (c.176C>G) is classified Uncertain significance in CWH43 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-07). AlphaMissense: likely benign (0.1136); Ultra-rare (popmax 0.0109%, nfe).

How common is CWH43 p.Pro59Arg (c.176C>G) in the general population?

CWH43 p.Pro59Arg (c.176C>G) is ultra-rare (popmax 0.0109%, nfe) (gnomAD).

What do computational predictors say about CWH43 p.Pro59Arg (c.176C>G)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

CWH43 p.Pro59Arg

c.176C>G · rs764506256 · VCV3079134

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -8.44	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 1.9	GERP 1.9, phastCons 0.005
Regional constraint	o/e 1.14	unconstrained · MANE · 5,112 bp · p 0.12 · regional, not allelic
Overall
CADD	21.1	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 0.0109% European (non-Finnish) · 129/1,179,448 alleles

Filtering AF 0.00936% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0088%

Overall 0.00837% 135/1,613,130 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0109%	9,143
Remaining individualsnot grpmax-eligible	0.0048%	20,816
Finnishnot grpmax-eligible	0.00313%	31,983
Admixed American	0.00167%	59,954

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: CWH43
Protein: p.Pro59Arg
Coding: c.176C>G
MANE Select: NM_025087
dbSNP: rs764506256
Type: single nucleotide variant
Location: chr4:48988609 (GRCh38)
Gene constraint: LOEUF 1.313 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.45

Full CWH43 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CWH43 p.Ala626Val Benign ★★ ⚠ same type
CWH43 p.Glu516Gln Benign ★★ same type
CWH43 p.Ile78Val Benign ★★ same type
CWH43 p.Ala190Thr Uncertain significance ★ ⚠ same type
CWH43 p.Ala246Val Uncertain significance ★ ⚠ same type
CWH43 p.Ala272Val Uncertain significance ★ ⚠ same type
CWH43 p.Ala273Val Uncertain significance ★ ⚠ same type
CWH43 p.Ala291Thr 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/cwh43-p-pro59arg (accessed [today's date]).

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