Is DSG4 p.Ile210Phe (c.628A>T) pathogenic?

DSG4 p.Ile210Phe (c.628A>T) is classified Uncertain significance in DSG4 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely benign (0.208); Very rare (popmax 0.005%, amr); Associated with hypotrichosis 6.

What condition is associated with DSG4 p.Ile210Phe (c.628A>T)?

DSG4 p.Ile210Phe (c.628A>T) is associated with hypotrichosis 6 (ClinVar).

How common is DSG4 p.Ile210Phe (c.628A>T) in the general population?

DSG4 p.Ile210Phe (c.628A>T) is very rare (popmax 0.005%, amr) (gnomAD).

How is Hypotrichosis simplex inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DSG4 p.Ile210Phe (c.628A>T)?

AlphaMissense predicts likely benign (score 0.208) — an in-silico prediction, not a clinical call.

DSG4 p.Ile210Phe

c.628A>T · rs749155221 · VCV326424

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.208 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypotrichosis 6

Computational evidence

Protein change
AlphaMissense	0.208	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -0.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 37 kb · p 0.015 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,962 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00366% 59/1,613,684 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,987
European (non-Finnish)	0.00458%	21,848
Remaining individualsnot grpmax-eligible	0.0016%	62,472
African / African-American	0.00133%	74,910

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.Ile210Phe
Coding: c.628A>T
MANE Select: NM_177986
dbSNP: rs749155221
Type: single nucleotide variant
Location: chr18:31390766 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.63
Residue 210: a UniProt-annotated variant site (in hypt6); the cadherin 2 domain

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

Disease context

hypotrichosis 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypotrichosis simplex (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood

Similar variants

DSG4 p.His386Gln Uncertain significance ★★ ⚠ same condition
DSG4 p.His902Arg Uncertain significance ★★ ⚠ same condition
DSG4 p.Tyr585His Uncertain significance ★★ ⚠ same condition
DSG4 c.*126G>A Benign/Likely benign ★★ same condition
DSG4 c.*31C>T Benign ★★ same condition
DSG4 p.Ala154Thr Benign/Likely benign ★★ ⚠ same condition
DSG4 p.Ile439Thr Benign/Likely benign ★★ ⚠ same condition
DSG4 p.Met1023Ile Benign/Likely benign ★★ 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/dsg4-p-ile210phe (accessed [today's date]).

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