Is KRT14 p.Arg446Cys (c.1336C>T) pathogenic?

KRT14 p.Arg446Cys (c.1336C>T) is classified Uncertain significance in KRT14 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-03). AlphaMissense: likely benign (0.2853); Ultra-rare (popmax 0.0166%, mid).

How common is KRT14 p.Arg446Cys (c.1336C>T) in the general population?

KRT14 p.Arg446Cys (c.1336C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about KRT14 p.Arg446Cys (c.1336C>T)?

AlphaMissense predicts likely benign (score 0.2853) — an in-silico prediction, not a clinical call.

KRT14 p.Arg446Cys

c.1336C>T · rs576427037 · VCV2995724

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2853 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2853	likely benign
REVEL	0.584	indeterminate
SaProt	LLR -8.98	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 4,396 bp · p 3e-05 · regional, not allelic
Overall
CADD	29.0	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 0.0166% Middle Eastern · 1/6,016 alleles

Filtering AF 0.00152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00082%

Overall 0.000895% 14/1,565,062 alleles · ultra-rare exomes 11/1,412,746 · genomes 3/152,316 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,016
Admixed American	0.00572%	17,494
Remaining individualsnot grpmax-eligible	0.00165%	60,748
African / African-American	0.00135%	73,812
South Asian	0.00118%	84,808
European (non-Finnish)	0.000606%	164,945

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: KRT14
Protein: p.Arg446Cys
Coding: c.1336C>T
MANE Select: NM_000526
dbSNP: rs576427037
Type: single nucleotide variant
Location: chr17:41582518 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.00 · 6 PDB
Residue 446: the 'disordered' region; the 'tail' region; the 'interaction with type i keratins and keratin filaments' region

Full KRT14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT14 p.Arg446Ser Uncertain significance ★ ⚠ same residue
KRT14 c.526-2A>C Likely pathogenic ★★ same type
KRT14 c.927+1G>A Pathogenic ★★ same type
KRT14 p.Arg125Cys Pathogenic ★★ same type
KRT14 p.Arg125His Pathogenic ★★ same type
KRT14 p.Arg125Leu Pathogenic ★★ same type
KRT14 p.Arg288Leu Pathogenic/Likely pathogenic ★★ same type
KRT14 p.Arg388Cys Pathogenic/Likely pathogenic ★★ 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/krt14-p-arg446cys (accessed [today's date]).

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