Is SHH p.Arg263= (c.789C>G) pathogenic?

SHH p.Arg263= (c.789C>G) is classified Likely benign in SHH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-01). Ultra-rare (popmax 0.0564%, afr); Associated with holoprosencephaly 3.

What condition is associated with SHH p.Arg263= (c.789C>G)?

SHH p.Arg263= (c.789C>G) is associated with holoprosencephaly 3 (ClinVar).

How common is SHH p.Arg263= (c.789C>G) in the general population?

SHH p.Arg263= (c.789C>G) is ultra-rare (popmax 0.0564%, afr) (gnomAD).

SHH p.Arg263=

c.789C>G · rs538266080 · VCV3036136

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0564%, afr)

Conditions

holoprosencephaly 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.67	GERP -1.9, phastCons 0.99
Overall
CADD	8.689	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0564% African / African-American · 42/74,514 alleles

Filtering AF 0.0428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0381%

Overall 0.00375% 59/1,574,016 alleles · ultra-rare exomes 22/1,421,738 · genomes 37/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0564%	1,774
Admixed American	0.0107%	9,379
Remaining individualsnot grpmax-eligible	0.00654%	15,297
European (non-Finnish)	0.000601%	166,407

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.Arg263=
Coding: c.789C>G
MANE Select: NM_000193
dbSNP: rs538266080
Type: single nucleotide variant
Location: chr7:155803500 (GRCh38)
Gene constraint: LOEUF 0.493 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.23 · 20 PDB
Residue 263: a UniProt-annotated variant site (in hpe3; sporadic)

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

Disease context

holoprosencephaly 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SHH p.Arg263_Ala269del Pathogenic same residue
SHH p.Arg72Ter Pathogenic ★★ same condition
SHH p.Asp222Asn Likely pathogenic ★★ same condition
SHH p.Leu266Phe Likely pathogenic ★★ same condition
SHH p.Leu271Pro Likely pathogenic ★★ same condition
SHH p.Pro347Arg Likely pathogenic ★★ same condition
SHH p.Pro347Leu Pathogenic/Likely pathogenic ★★ same condition
SHH p.Ser436Ter Pathogenic/Likely pathogenic ★★ 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-arg263 (accessed [today's date]).

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