Is DSC2 p.Val49Phe (c.145G>T) pathogenic?

DSC2 p.Val49Phe (c.145G>T) is classified Uncertain significance in DSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-19). AlphaMissense: likely benign (0.3375); Very rare (popmax 0.00502%, amr); Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.Val49Phe (c.145G>T)?

DSC2 p.Val49Phe (c.145G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is DSC2 p.Val49Phe (c.145G>T) in the general population?

DSC2 p.Val49Phe (c.145G>T) is very rare (popmax 0.00502%, amr) (gnomAD).

What do computational predictors say about DSC2 p.Val49Phe (c.145G>T)?

AlphaMissense predicts likely benign (score 0.3375) — an in-silico prediction, not a clinical call.

DSC2 p.Val49Phe

c.145G>T · VCV4824033

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3375 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00502%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3375	likely benign
REVEL	0.321	indeterminate
SaProt	LLR -14.26	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.49	GERP -4, phastCons 0.058
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	18.93	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 0.00502% Admixed American · 3/59,770 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.000187% 3/1,605,688 alleles · very rare exomes 3/1,453,670 · genomes 0/152,018 · 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: DSC2
Protein: p.Val49Phe
Coding: c.145G>T
MANE Select: NM_024422
Type: single nucleotide variant
Location: chr18:31093568 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB

Full DSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DSC2 p.Val49Ala Uncertain significance ★★ ⚠ same residue
DSC2 c.1521-1G>A Likely pathogenic ★★ same condition
DSC2 c.354+2T>A Likely pathogenic ★★ same condition
DSC2 p.Gln620Ter Pathogenic ★★ same condition
DSC2 p.Tyr221Ter Pathogenic/Likely pathogenic ★★ same condition
DSC2 c.2508+1G>A Uncertain significance ★★ same condition
DSC2 c.355-3G>T Uncertain significance ★★ same condition
DSC2 p.Ala61Glu 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/dsc2-p-val49phe (accessed [today's date]).

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