Is PTCH2 p.Ala574Ser (c.1720G>T) pathogenic?

PTCH2 p.Ala574Ser (c.1720G>T) is classified Uncertain significance in PTCH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.0763); Ultra-rare (popmax 0.0164%, mid); Associated with nevoid basal cell carcinoma syndrome.

What condition is associated with PTCH2 p.Ala574Ser (c.1720G>T)?

PTCH2 p.Ala574Ser (c.1720G>T) is associated with nevoid basal cell carcinoma syndrome (ClinVar).

How common is PTCH2 p.Ala574Ser (c.1720G>T) in the general population?

PTCH2 p.Ala574Ser (c.1720G>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PTCH2 p.Ala574Ser (c.1720G>T)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

PTCH2 p.Ala574Ser

c.1720G>T · rs779477101 · VCV664994

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nevoid basal cell carcinoma syndrome

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -5.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.39	acceptor gain · deltas
Pangolin	Δ0.31	gain · loss 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.3	GERP 0.51, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 21 kb · p 3.4e-06 · regional, not allelic
Overall
CADD	18.54	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00143% 23/1,613,472 alleles · ultra-rare exomes 22/1,461,230 · genomes 1/152,242 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00178%	56,192
Remaining individualsnot grpmax-eligible	0.0016%	62,478

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.Ala574Ser
Coding: c.1720G>T
MANE Select: NM_003738
dbSNP: rs779477101
Type: single nucleotide variant
Location: chr1:44828181 (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-ala574ser (accessed [today's date]).

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