Is DSP p.Leu192Ser (c.575T>C) pathogenic?

DSP p.Leu192Ser (c.575T>C) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-11-16). AlphaMissense: ambiguous (0.5066); Very rare (popmax 0.0033%, sas); Associated with cardiomyopathy.

How common is DSP p.Leu192Ser (c.575T>C) in the general population?

DSP p.Leu192Ser (c.575T>C) is very rare (popmax 0.0033%, sas) (gnomAD).

What do computational predictors say about DSP p.Leu192Ser (c.575T>C)?

AlphaMissense predicts ambiguous (score 0.5066) — an in-silico prediction, not a clinical call.

DSP p.Leu192Ser

Q: What condition is associated with DSP p.Leu192Ser (c.575T>C)?

DSP p.Leu192Ser (c.575T>C) is associated with cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma, arrhythmogenic right ventricular dysplasia 8 (ClinVar).

c.575T>C · rs765310938 · VCV2025682

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5066 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.5066	ambiguous
REVEL	0.688	pathogenic-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	26.0	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 0.0033% South Asian · 3/91,012 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000205% 3/1,460,556 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: DSP
Protein: p.Leu192Ser
Coding: c.575T>C
MANE Select: NM_004415
dbSNP: rs765310938
Type: single nucleotide variant
Location: chr6:7559378 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 192: 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)

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

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

DSP p.Leu192Phe Uncertain significance ★★ same residue
DSP p.Leu192Trp Uncertain significance ★ ⚠ same residue
DSP p.Leu192= 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-leu192ser (accessed [today's date]).

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