Is SHH p.Phe199= (c.597C>T) pathogenic?

SHH p.Phe199= (c.597C>T) is classified Likely benign in SHH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). Ultra-rare (popmax 0.01%, amr); Associated with holoprosencephaly 3.

What condition is associated with SHH p.Phe199= (c.597C>T)?

SHH p.Phe199= (c.597C>T) is associated with holoprosencephaly 3 (ClinVar).

How common is SHH p.Phe199= (c.597C>T) in the general population?

SHH p.Phe199= (c.597C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

SHH p.Phe199=

c.597C>T · rs999942157 · VCV1673533

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

holoprosencephaly 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP -2.4, phastCons 1
Overall
CADD	13.21	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/59,916 alleles

Filtering AF 0.00429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00296%

Overall 0.000876% 14/1,597,780 alleles · ultra-rare exomes 13/1,445,534 · genomes 1/152,246 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,986
Remaining individualsnot grpmax-eligible	0.00642%	15,572
East Asian	0.00223%	44,834
European (non-Finnish)	0.000254%	393,167

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.Phe199=
Coding: c.597C>T
MANE Select: NM_000193
dbSNP: rs999942157
Type: single nucleotide variant
Location: chr7:155803692 (GRCh38)
Gene constraint: LOEUF 0.493 · pLI 0.98 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.23 · 20 PDB
Residue 199: a UniProt-annotated variant site (in hpe3)

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.Phe199_Gly201del Likely 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-phe199 (accessed [today's date]).

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