Is PTCH2 p.Val993Ala (c.2978T>C) pathogenic?

PTCH2 p.Val993Ala (c.2978T>C) is classified Uncertain significance in PTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-07). AlphaMissense: ambiguous (0.3621); Very rare (popmax 0.000339%, nfe); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Val993Ala (c.2978T>C)?

PTCH2 p.Val993Ala (c.2978T>C) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH2 p.Val993Ala (c.2978T>C) in the general population?

PTCH2 p.Val993Ala (c.2978T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about PTCH2 p.Val993Ala (c.2978T>C)?

AlphaMissense predicts ambiguous (score 0.3621) — an in-silico prediction, not a clinical call.

PTCH2 p.Val993Ala

c.2978T>C · VCV3427356

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.3621	ambiguous
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -8.54	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,034 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,962 alleles · very rare exomes 3/1,461,806 · genomes 1/152,156 · 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: PTCH2
Protein: p.Val993Ala
Coding: c.2978T>C
MANE Select: NM_003738
Type: single nucleotide variant
Location: chr1:44826386 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25

Full PTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nevoid basal cell carcinoma syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PTCH2 c.2976+2T>C Uncertain significance ★★ same condition
PTCH2 c.526-2A>G Uncertain significance ★★ same condition
PTCH2 c.618-6C>A Uncertain significance ★★ same condition
PTCH2 p.Ala1052Thr Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala1090Val Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala203Val Uncertain significance ★★ same condition
PTCH2 p.Ala21Thr Uncertain significance ★★ ⚠ same condition
PTCH2 p.Ala371Gly 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/ptch2-p-val993ala (accessed [today's date]).

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