Is DSC3 p.Pro740Ser (c.2218C>T) pathogenic?

DSC3 p.Pro740Ser (c.2218C>T) is classified Likely benign in DSC3 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-27). AlphaMissense: likely pathogenic (0.6277); Rare (popmax 0.381%, nfe).

How common is DSC3 p.Pro740Ser (c.2218C>T) in the general population?

DSC3 p.Pro740Ser (c.2218C>T) is rare (popmax 0.381%, nfe) (gnomAD).

What do computational predictors say about DSC3 p.Pro740Ser (c.2218C>T)?

AlphaMissense predicts likely pathogenic (score 0.6277) — an in-silico prediction, not a clinical call.

DSC3 p.Pro740Ser

c.2218C>T · rs114935867 · VCV3033281

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6277 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.381%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6277	likely pathogenic
REVEL	0.293	indeterminate
SaProt	LLR -5.43	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; 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	28.2	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 0.381% European (non-Finnish) · 4,485/1,177,796 alleles

Filtering AF 0.371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.368%

Overall 0.319% 5,131/1,610,450 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.543%	184
European (non-Finnish)grpmax	0.381%	263
Remaining individualsnot grpmax-eligible	0.218%	458
Middle Eastern	0.0993%	1,007
Admixed American	0.0884%	1,131
South Asian	0.0641%	1,560
African / African-American	0.0574%	1,743
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,385

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro740Ser
Coding: c.2218C>T
MANE Select: NM_024422 · reported on NM_001941
dbSNP: rs114935867
Type: single nucleotide variant
Location: chr18:31001635 (GRCh38)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 740: 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.Ser740Ter Likely pathogenic ★★ same residue
DSC2 p.Ser740Pro 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

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-pro740ser (accessed [today's date]).

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