Is DSC3 p.Pro182His (c.545C>A) pathogenic?

DSC3 p.Pro182His (c.545C>A) is classified Uncertain significance in DSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-09). AlphaMissense: likely pathogenic (0.9435); Very rare (popmax 0.0022%, sas).

How common is DSC3 p.Pro182His (c.545C>A) in the general population?

DSC3 p.Pro182His (c.545C>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about DSC3 p.Pro182His (c.545C>A)?

AlphaMissense predicts likely pathogenic (score 0.9435) — an in-silico prediction, not a clinical call.

DSC3 p.Pro182His

c.545C>A · VCV3273795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9435 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9435	likely pathogenic · top 9% in DSC3
REVEL	0.534	indeterminate
SaProt	LLR -12.06	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0022% South Asian · 2/91,044 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000496% 8/1,612,858 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,522
Admixed American	0.00167%	59,900
Remaining individualsnot grpmax-eligible	0.0016%	62,440
African / African-American	0.00134%	74,798
European (non-Finnish)	0.000254%	393,110

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: DSC3
Protein: p.Pro182His
Coding: c.545C>A
MANE Select: NM_024422 · reported on NM_001941
Type: single nucleotide variant
Location: chr18:31025845 (GRCh38)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 182: a β-strand; the cadherin 1 domain

Full DSC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DSC2 p.Pro182Leu Uncertain significance ★ ⚠ same residue
DSC2 c.1521-1G>A Likely pathogenic ★★ same type
DSC2 c.1664-1G>A Likely pathogenic ★★ same type
DSC2 c.354+2T>A Likely pathogenic ★★ same type
DSC2 c.355-1G>A Likely pathogenic ★★ same type
DSC2 p.Gln554Ter Pathogenic ★★ same type
DSC2 p.Gln620Ter Pathogenic ★★ same type
DSC2 p.Glu127Ter Pathogenic/Likely pathogenic ★★ same type

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/dsc3-p-pro182his (accessed [today's date]).

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