Is DSG4 p.Phe25Ser (c.74T>C) pathogenic?

DSG4 p.Phe25Ser (c.74T>C) is classified Uncertain significance in DSG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-08). AlphaMissense: likely pathogenic (0.8229); Very rare (popmax 0.000428%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DSG4 p.Phe25Ser (c.74T>C)?

DSG4 p.Phe25Ser (c.74T>C) is associated with Inborn genetic diseases (ClinVar).

How common is DSG4 p.Phe25Ser (c.74T>C) in the general population?

DSG4 p.Phe25Ser (c.74T>C) is very rare (popmax 0.000428%, nfe) (gnomAD).

What do computational predictors say about DSG4 p.Phe25Ser (c.74T>C)?

AlphaMissense predicts likely pathogenic (score 0.8229) — an in-silico prediction, not a clinical call.

DSG4 p.Phe25Ser

c.74T>C · VCV3505460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8229 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000428%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8229	likely pathogenic
REVEL	0.378	indeterminate
SaProt	LLR -4.16	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.8	GERP 2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 37 kb · p 0.015 · regional, not allelic
Overall
CADD	26.4	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 0.000428% European (non-Finnish) · 5/1,168,246 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000313% 5/1,595,250 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: DSG4
Protein: p.Phe25Ser
Coding: c.74T>C
Type: single nucleotide variant
Location: chr18:31385161 (GRCh38)

Full DSG4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/dsg4-p-phe25ser (accessed [today's date]).

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