Is KRT74 p.Phe274Ser (c.821T>C) pathogenic?

KRT74 p.Phe274Ser (c.821T>C) is classified Conflicting classifications of pathogenicity in KRT74 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.6841); Common (popmax 7.85%, sas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant wooly hair.

What condition is associated with KRT74 p.Phe274Ser (c.821T>C)?

KRT74 p.Phe274Ser (c.821T>C) is associated with autosomal dominant wooly hair, ectodermal dysplasia 4, hair/nail type, hypotrichosis 3 (ClinVar).

How is Woolly hair inherited?

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

What do computational predictors say about KRT74 p.Phe274Ser (c.821T>C)?

AlphaMissense predicts likely pathogenic (score 0.6841) — an in-silico prediction, not a clinical call.

KRT74 p.Phe274Ser

Q: How common is KRT74 p.Phe274Ser (c.821T>C) in the general population?

KRT74 p.Phe274Ser (c.821T>C) is common (popmax 7.85%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.821T>C · rs147962513 · VCV96741

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.6841 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 7.85%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant wooly hair

Computational evidence

Protein change
AlphaMissense	0.6841	likely pathogenic · top 8% in KRT74
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -11.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 6,805 bp · p 0.074 · regional, not allelic
Overall
CADD	29.3	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 7.85% South Asian · 7,137/90,950 alleles

Filtering AF 7.69% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.63%

Overall 0.471% 7,586/1,611,700 alleles · common exomes 7,164/1,459,442 · genomes 422/152,258 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	7.85%	13
Remaining individualsnot grpmax-eligible	0.506%	198
Middle Eastern	0.363%	275
African / African-American	0.016%	6,249
Admixed American	0.015%	6,669
East Asian	0.0111%	8,972
European (non-Finnish)	0.00722%	13,857

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: KRT74
Protein: p.Phe274Ser
Coding: c.821T>C
MANE Select: NM_175053
dbSNP: rs147962513
Type: single nucleotide variant
Location: chr12:52571381 (GRCh38)
Gene constraint: LOEUF 1.278 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.11
Residue 274: the if rod domain; a UniProt-annotated variant site (in ectd7; autosomal recessive); the 'coil 1b' region

Full KRT74 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant wooly hair — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ectodermal dysplasia 4, hair/nail type hypotrichosis 3 ectodermal dysplasia 7, hair/nail type

For Woolly hair (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

KRT74 p.Ala410Thr Uncertain significance ★★ ⚠ same condition
KRT74 p.Arg69Trp Uncertain significance ★★ ⚠ same condition
KRT74 p.Gln285Ter Conflicting classifications of pathogenicity ★ same condition
KRT74 c.1391-1G>A Pathogenic same condition
KRT74 p.Asn148Lys Pathogenic same condition
KRT74 p.Asp482Asn Pathogenic ⚠ same condition
KRT74 p.Arg141Gln Uncertain significance ★★ ⚠ same type
KRT74 p.Arg346Gln Uncertain significance ★★ ⚠ same type

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/krt74-p-phe274ser (accessed [today's date]).

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