Is DSP p.Thr1319Ser (c.3956C>G) pathogenic?

DSP p.Thr1319Ser (c.3956C>G) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-23). AlphaMissense: likely benign (0.2341); Ultra-rare (popmax 0.0736%, sas); Associated with cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis.

What condition is associated with DSP p.Thr1319Ser (c.3956C>G)?

DSP p.Thr1319Ser (c.3956C>G) is associated with cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Thr1319Ser (c.3956C>G) in the general population?

DSP p.Thr1319Ser (c.3956C>G) is ultra-rare (popmax 0.0736%, sas) (gnomAD).

How is Erythrokeratodermia-cardiomyopathy syndrome inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DSP p.Thr1319Ser (c.3956C>G)?

AlphaMissense predicts likely benign (score 0.2341) — an in-silico prediction, not a clinical call.

DSP p.Thr1319Ser

c.3956C>G · rs138599871 · VCV179434

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2341 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0736%, sas)

Conditions

cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

Computational evidence

Protein change
AlphaMissense	0.2341	likely benign
REVEL	0.357	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.0024 · regional, not allelic
Overall
CADD	22.3	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 0.0736% South Asian · 67/91,084 alleles

Filtering AF 0.0593% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.00459% 74/1,613,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0736%	1,359
Admixed American	0.00667%	14,999
Remaining individualsnot grpmax-eligible	0.0048%	20,826

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: DSP
Protein: p.Thr1319Ser
Coding: c.3956C>G
MANE Select: NM_004415
dbSNP: rs138599871
Type: single nucleotide variant
Location: chr6:7580146 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1319: a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); the 'central fibrous rod domain' region; the 'binds to telomeres' region; a UniProt-annotated variant site (in arvd8; likely pathogenic; results in an unstable protein that forms perinuclear aggregates); a UniProt-annotated variant site (in arvd8 and dcwhkta; uncertain significance); a UniProt-annotated variant site (in arvd8)

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

Disease context

cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy arrhythmogenic cardiomyopathy with wooly hair and keratoderma arrhythmogenic right ventricular dysplasia 8

For Erythrokeratodermia-cardiomyopathy syndrome (Orphanet):

Inheritance: Not applicable
Onset: Neonatal

Similar variants

DSP p.Thr1319= Likely benign ★★ same residue
DSP p.Thr1319Ile Conflicting classifications of pathogenicity ★ same residue
DSP c.1141-2A>T Likely pathogenic ★★ same condition
DSP c.1266+2T>C Likely pathogenic ★★ same condition
DSP c.1574+1G>A Likely pathogenic ★★ same condition
DSP c.2130+1G>A Pathogenic/Likely pathogenic ★★ same condition
DSP c.2297+1G>A Likely pathogenic ★★ same condition
DSP c.2298-1G>C Likely pathogenic ★★ 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/dsp-p-thr1319ser (accessed [today's date]).

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