Is DSC1 p.Val565Ala (c.1694T>C) pathogenic?

DSC1 p.Val565Ala (c.1694T>C) is classified Uncertain significance in DSC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-30). AlphaMissense: likely pathogenic (0.7919); Ultra-rare (popmax 0.0304%, nfe).

How common is DSC1 p.Val565Ala (c.1694T>C) in the general population?

DSC1 p.Val565Ala (c.1694T>C) is ultra-rare (popmax 0.0304%, nfe) (gnomAD).

What do computational predictors say about DSC1 p.Val565Ala (c.1694T>C)?

AlphaMissense predicts likely pathogenic (score 0.7919) — an in-silico prediction, not a clinical call.

DSC1 p.Val565Ala

c.1694T>C · rs139800857 · VCV2527203

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7919 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0304%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7919	likely pathogenic
REVEL	0.398	indeterminate
SaProt	LLR -12.36	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 32 kb · p 0.23 · regional, not allelic
Overall
CADD	23.1	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 0.0304% European (non-Finnish) · 359/1,179,088 alleles

Filtering AF 0.0278% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0268%

Overall 0.023% 371/1,612,778 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0304%	3,284
Remaining individualsnot grpmax-eligible	0.016%	6,244
Admixed American	0.00167%	59,870
African / African-American	0.00133%	75,008

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.Val565Ala
Coding: c.1694T>C
MANE Select: NM_024421
dbSNP: rs139800857
Type: single nucleotide variant
Location: chr18:31134754 (GRCh38)
Gene constraint: LOEUF 0.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.16 · 1 PDB
Residue 565: a β-strand; the cadherin 4 domain

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-val565ala (accessed [today's date]).

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