Is DSP p.Gln331Pro (c.992A>C) pathogenic?

DSP p.Gln331Pro (c.992A>C) is classified Uncertain significance in DSP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-06-30). AlphaMissense: likely pathogenic (0.9584); Very rare (popmax 0.00127%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSP p.Gln331Pro (c.992A>C)?

DSP p.Gln331Pro (c.992A>C) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Gln331Pro (c.992A>C) in the general population?

DSP p.Gln331Pro (c.992A>C) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about DSP p.Gln331Pro (c.992A>C)?

AlphaMissense predicts likely pathogenic (score 0.9584) — an in-silico prediction, not a clinical call.

DSP p.Gln331Pro

c.992A>C · rs746517026 · VCV228654

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9584 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9584	likely pathogenic · top 9% in DSP
REVEL	0.55	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	26.6	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 0.00127% European (non-Finnish) · 15/1,180,040 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00105% 17/1,613,966 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)grpmax	0.00127%	78,670

Remaining individuals 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: DSP
Protein: p.Gln331Pro
Coding: c.992A>C
MANE Select: NM_004415
dbSNP: rs746517026
Type: single nucleotide variant
Location: chr6:7566429 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 331: 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.Gln331Ter Pathogenic ★★ same residue
DSP p.Gln331Arg 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-gln331pro (accessed [today's date]).

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