Is WHRN p.Pro99Arg (c.296C>G) pathogenic?

WHRN p.Pro99Arg (c.296C>G) is classified Uncertain significance in WHRN (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-04). AlphaMissense: likely pathogenic (0.9876); Very rare (popmax 0.000763%, nfe).

How common is WHRN p.Pro99Arg (c.296C>G) in the general population?

WHRN p.Pro99Arg (c.296C>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about WHRN p.Pro99Arg (c.296C>G)?

AlphaMissense predicts likely pathogenic (score 0.9876) — an in-silico prediction, not a clinical call.

WHRN p.Pro99Arg

c.296C>G · VCV4904224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9876	likely pathogenic · top 4% in WHRN
REVEL	0.488	indeterminate
SaProt	LLR -11.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 0.73, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 102 kb · p 0.96 · regional, not allelic
Overall
CADD	33.0	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 0.000763% European (non-Finnish) · 9/1,179,816 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000621% 10/1,609,276 alleles · very rare exomes 8/1,457,012 · genomes 2/152,264 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,436
European (non-Finnish)grpmax	0.000763%	131,091

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: WHRN
Protein: p.Pro99Arg
Coding: c.296C>G
MANE Select: NM_015404
Type: single nucleotide variant
Location: chr9:114504506 (GRCh38)
Gene constraint: LOEUF 0.808 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 59.39 · 5 PDB

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

Similar variants

WHRN p.Pro99= Likely benign ★ same residue
WHRN c.1203+2T>C Likely pathogenic ★★ same type
WHRN c.1417-1G>A Pathogenic/Likely pathogenic ★★ same type
WHRN p.Arg778Ter Pathogenic ★★ same type
WHRN p.Gln187Ter Pathogenic/Likely pathogenic ★★ same type
WHRN p.Trp374Ter Pathogenic/Likely pathogenic ★★ same type
WHRN c.*156G>A Uncertain significance ★★ same type
WHRN p.Ala207Ser 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/whrn-p-pro99arg (accessed [today's date]).

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