Is SHH p.Pro41Arg (c.122C>G) pathogenic?

SHH p.Pro41Arg (c.122C>G) is classified Uncertain significance in SHH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely pathogenic (0.9737); Very rare (popmax 8.47e-05%, nfe).

How common is SHH p.Pro41Arg (c.122C>G) in the general population?

SHH p.Pro41Arg (c.122C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SHH p.Pro41Arg (c.122C>G)?

AlphaMissense predicts likely pathogenic (score 0.9737) — an in-silico prediction, not a clinical call.

SHH p.Pro41Arg

c.122C>G · VCV3365111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9737	likely pathogenic
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -15.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 281 bp · p 0.00019 · regional, not allelic
Overall
CADD	32.0	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 8.47e-05% European (non-Finnish) · 1/1,180,040 alleles

Overall 6.2e-05% 1/1,614,196 alleles · very rare exomes 1/1,461,890 · genomes 0/152,306 · joint denominator

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: SHH
Protein: p.Pro41Arg
Coding: c.122C>G
MANE Select: NM_000193
Type: single nucleotide variant
Location: chr7:155812001 (GRCh38)
Gene constraint: LOEUF 0.493 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.23 · 20 PDB
Residue 41: an α-helix

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

Similar variants

SHH p.Pro41Ala Uncertain significance ★ ⚠ same residue
SHH p.Pro41fs Pathogenic ★ same residue
SHH c.562+1G>A Pathogenic ★★ same type
SHH p.Arg72Ter Pathogenic ★★ same type
SHH p.Asp222Asn Likely pathogenic ★★ same type
SHH p.Cys198Arg Pathogenic/Likely pathogenic ★★ same type
SHH p.Cys198Ser Likely pathogenic ★★ same type
SHH p.Leu266Phe Likely pathogenic ★★ 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/shh-p-pro41arg (accessed [today's date]).

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