Is DSC1 p.Pro725Ser (c.2173C>T) pathogenic?

DSC1 p.Pro725Ser (c.2173C>T) is classified Uncertain significance in DSC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-28). AlphaMissense: ambiguous (0.3713); Ultra-rare (popmax 0.0117%, amr).

How common is DSC1 p.Pro725Ser (c.2173C>T) in the general population?

DSC1 p.Pro725Ser (c.2173C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about DSC1 p.Pro725Ser (c.2173C>T)?

AlphaMissense predicts ambiguous (score 0.3713) — an in-silico prediction, not a clinical call.

DSC1 p.Pro725Ser

c.2173C>T · rs769486740 · VCV2309718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3713 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3713	ambiguous
REVEL	0.28	benign-leaning
SaProt	LLR -6.12	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense 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
Regional constraint	o/e 1.04	unconstrained · MANE · 32 kb · p 0.23 · regional, not allelic
Overall
CADD	24.2	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 0.0117% Admixed American · 7/59,946 alleles

Filtering AF 0.00544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000434% 7/1,613,226 alleles · ultra-rare

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: DSC1
Protein: p.Pro725Ser
Coding: c.2173C>T
MANE Select: NM_024421
dbSNP: rs769486740
Type: single nucleotide variant
Location: chr18:31132633 (GRCh38)
Gene constraint: LOEUF 0.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16 · 1 PDB

Full DSC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DSC1 p.Ile200Thr Benign ★★ ⚠ same type
DSC1 p.Met659Arg Benign ★★ same type
DSC1 p.Thr710= Benign ★★ same type
DSC1 p.Ala128Pro Uncertain significance ★ ⚠ same type
DSC1 p.Ala209Val Uncertain significance ★ ⚠ same type
DSC1 p.Ala221Glu Uncertain significance ★ ⚠ same type
DSC1 p.Ala239Thr Uncertain significance ★ ⚠ same type
DSC1 p.Ala574Thr Uncertain significance ★ ⚠ 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/dsc1-p-pro725ser (accessed [today's date]).

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