Is DSP p.Leu142Phe (c.424C>T) pathogenic?

DSP p.Leu142Phe (c.424C>T) is classified Uncertain significance in DSP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-03-19). AlphaMissense: ambiguous (0.5209); Ultra-rare (popmax 0.0147%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DSP p.Leu142Phe (c.424C>T)?

DSP p.Leu142Phe (c.424C>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Leu142Phe (c.424C>T) in the general population?

DSP p.Leu142Phe (c.424C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about DSP p.Leu142Phe (c.424C>T)?

AlphaMissense predicts ambiguous (score 0.5209) — an in-silico prediction, not a clinical call.

DSP p.Leu142Phe

c.424C>T · rs373769397 · VCV199849

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.5209 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5209	ambiguous
REVEL	0.379	indeterminate
SaProt	LLR -7.03	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1	GERP 0.96, phastCons 0.52
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	23.2	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 0.0147% African / African-American · 11/74,908 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00204% 33/1,613,764 alleles · ultra-rare exomes 20/1,461,600 · genomes 13/152,164 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,810
South Asian	0.011%	9,108
Admixed American	0.00833%	12,000
Remaining individualsnot grpmax-eligible	0.00801%	12,490
East Asian	0.00223%	44,898
European (non-Finnish)	8.47e-05%	1,180,002

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.Leu142Phe
Coding: c.424C>T
MANE Select: NM_004415
dbSNP: rs373769397
Type: single nucleotide variant
Location: chr6:7559227 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 142: the 'globular 1' region; the 'interaction with mapre1' region; the 'interaction with jup and pkp2' region; a UniProt-annotated variant site (in arvd8; 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 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
DSP c.2298-2A>C Pathogenic/Likely pathogenic ★★ same condition
DSP c.2437-1G>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-leu142phe (accessed [today's date]).

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