Is DSP p.Ile368Phe (c.1102A>T) pathogenic?

DSP p.Ile368Phe (c.1102A>T) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-05-10). AlphaMissense: likely pathogenic (0.9182); Very rare (popmax 0.000254%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSP p.Ile368Phe (c.1102A>T)?

DSP p.Ile368Phe (c.1102A>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Ile368Phe (c.1102A>T) in the general population?

DSP p.Ile368Phe (c.1102A>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about DSP p.Ile368Phe (c.1102A>T)?

AlphaMissense predicts likely pathogenic (score 0.9182) — an in-silico prediction, not a clinical call.

DSP p.Ile368Phe

c.1102A>T · rs794728112 · VCV199859

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9182 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9182	likely pathogenic
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	26.8	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 0.000254% European (non-Finnish) · 3/1,180,032 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,984 alleles · very rare exomes 2/1,461,796 · genomes 1/152,188 · 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: DSP
Protein: p.Ile368Phe
Coding: c.1102A>T
MANE Select: NM_004415
dbSNP: rs794728112
Type: single nucleotide variant
Location: chr6:7567411 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 368: an α-helix; the 'globular 1' region; the 'interaction with mapre1' region; the 'interaction with jup and pkp2' region; the 'interaction with pkp1' region; a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); 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)

Full DSP 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

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

Similar variants

DSP p.Ile368Val Uncertain significance ★★ same residue
DSP p.Ile368Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
DSP p.Ile368= Likely benign ★ 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

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-ile368phe (accessed [today's date]).

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