Is KRT4 p.Leu55Pro (c.164T>C) pathogenic?

KRT4 p.Leu55Pro (c.164T>C) is classified Uncertain significance in KRT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-17). AlphaMissense: likely benign (0.239); Very rare (popmax 0.00847%, sas); Associated with Inborn genetic diseases.

What condition is associated with KRT4 p.Leu55Pro (c.164T>C)?

KRT4 p.Leu55Pro (c.164T>C) is associated with Inborn genetic diseases (ClinVar).

How common is KRT4 p.Leu55Pro (c.164T>C) in the general population?

KRT4 p.Leu55Pro (c.164T>C) is very rare (popmax 0.00847%, sas) (gnomAD).

What do computational predictors say about KRT4 p.Leu55Pro (c.164T>C)?

AlphaMissense predicts likely benign (score 0.239) — an in-silico prediction, not a clinical call.

KRT4 p.Leu55Pro

c.164T>C · rs1217672254 · VCV2277456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00847%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.239	likely benign
REVEL	0.49	indeterminate
SaProt	LLR -7.50	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,986 bp · p 0.83 · regional, not allelic
Overall
CADD	23.5	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 0.00847% South Asian · 5/59,020 alleles

Filtering AF 0.00327% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.000867% 10/1,153,728 alleles · very rare exomes 9/1,122,004 · genomes 1/31,724 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00847%	11,804
Remaining individualsnot grpmax-eligible	0.00491%	20,359
European (non-Finnish)	0.000322%	310,754

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: KRT4
Protein: p.Leu55Pro
Coding: c.164T>C
MANE Select: NM_002272
dbSNP: rs1217672254
Type: single nucleotide variant
Location: chr12:52813895 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77
Residue 55: the 'head' region

Full KRT4 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

Similar variants

KRT4 p.Leu55= Likely benign ★ same residue
KRT4 p.Ala106Gly Uncertain significance ★★ ⚠ same condition
KRT4 p.Asp153Asn Uncertain significance ★★ ⚠ same condition
KRT4 p.Asp247Glu Uncertain significance ★★ same condition
KRT4 p.His398Tyr Likely benign ★★ same condition
KRT4 p.Ala106Thr Uncertain significance ★ ⚠ same condition
KRT4 p.Ala20Asp Uncertain significance ★ ⚠ same condition
KRT4 p.Ala278Glu Uncertain significance ★ ⚠ 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/krt4-p-leu55pro (accessed [today's date]).

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