Is SHH p.Pro293Arg (c.878C>G) pathogenic?

SHH p.Pro293Arg (c.878C>G) is classified Uncertain significance in SHH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-24). AlphaMissense: likely benign (0.0543); Ultra-rare (popmax 0.0215%, mid); Associated with Inborn genetic diseases.

What condition is associated with SHH p.Pro293Arg (c.878C>G)?

SHH p.Pro293Arg (c.878C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SHH p.Pro293Arg (c.878C>G) in the general population?

SHH p.Pro293Arg (c.878C>G) is ultra-rare (popmax 0.0215%, mid) (gnomAD).

What do computational predictors say about SHH p.Pro293Arg (c.878C>G)?

AlphaMissense predicts likely benign (score 0.0543) — an in-silico prediction, not a clinical call.

SHH p.Pro293Arg

c.878C>G · VCV3795635

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0543 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0215%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0543	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -6.16	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 0.26	GERP -1.9, phastCons 0.002
Regional constraint	o/e 0.99	unconstrained · MANE · 566 bp · p 0.91 · regional, not allelic
Overall
CADD	5.506	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 0.0215% Middle Eastern · 1/4,648 alleles

Filtering AF 0.00977% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00765%

Overall 0.000856% 13/1,519,534 alleles · ultra-rare exomes 6/1,367,488 · genomes 7/152,046 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0215%	4,648
African / African-American	0.0171%	5,862

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.Pro293Arg
Coding: c.878C>G
MANE Select: NM_000193
Type: single nucleotide variant
Location: chr7:155803411 (GRCh38)
Gene constraint: LOEUF 0.493 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.23 · 20 PDB
Residue 293: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SHH p.Pro293= Likely benign ★ same residue
SHH p.Tyr253Ter Pathogenic/Likely pathogenic ★★ same condition
SHH p.Ala5Pro Uncertain significance ★★ ⚠ same condition
SHH p.Asn79Ser Uncertain significance ★★ ⚠ same condition
SHH p.Asp245Asn Uncertain significance ★★ ⚠ same condition
SHH p.Asp322Glu Uncertain significance ★★ ⚠ same condition
SHH p.Glu368Lys Uncertain significance ★★ ⚠ same condition
SHH p.Gly283Arg 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/shh-p-pro293arg (accessed [today's date]).

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