Is DSC3 p.Phe723Leu (c.2167T>C) pathogenic?

DSC3 p.Phe723Leu (c.2167T>C) is classified Uncertain significance in DSC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely pathogenic (0.671); Very rare (popmax 0.00017%, nfe).

How common is DSC3 p.Phe723Leu (c.2167T>C) in the general population?

DSC3 p.Phe723Leu (c.2167T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about DSC3 p.Phe723Leu (c.2167T>C)?

AlphaMissense predicts likely pathogenic (score 0.671) — an in-silico prediction, not a clinical call.

DSC3 p.Phe723Leu

c.2167T>C · rs761772439 · VCV2484870

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.671	likely pathogenic
REVEL	0.135	moderately benign-leaning
SaProt	LLR -4.84	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.77, phastCons 1
Overall
CADD	18.56	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 0.00017% European (non-Finnish) · 2/1,178,452 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,458,752 alleles · very 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: DSC3
Protein: p.Phe723Leu
Coding: c.2167T>C
MANE Select: NM_024422 · reported on NM_001941
dbSNP: rs761772439
Type: single nucleotide variant
Location: chr18:31001686 (GRCh38)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 723: a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart)

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

Similar variants

DSC2 p.Lys723Glu 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-phe723leu (accessed [today's date]).

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