Is KRT2 p.Pro138Ser (c.412C>T) pathogenic?

KRT2 p.Pro138Ser (c.412C>T) is classified Uncertain significance in KRT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-05). AlphaMissense: likely benign (0.1249); Ultra-rare (popmax 0.0165%, mid).

How common is KRT2 p.Pro138Ser (c.412C>T) in the general population?

KRT2 p.Pro138Ser (c.412C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about KRT2 p.Pro138Ser (c.412C>T)?

AlphaMissense predicts likely benign (score 0.1249) — an in-silico prediction, not a clinical call.

KRT2 p.Pro138Ser

c.412C>T · rs1279729635 · VCV2958013

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1249 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1249	likely benign
REVEL	0.287	benign-leaning
SaProt	LLR -8.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.4	GERP -0.15, phastCons 0.86
Regional constraint	o/e 1.08	unconstrained · MANE · 7,120 bp · p 0.023 · regional, not allelic
Overall
CADD	16.06	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 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000124% 2/1,613,704 alleles · ultra-rare exomes 2/1,461,876 · genomes 0/151,828 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	8.48e-05%	1,179,933

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: KRT2
Protein: p.Pro138Ser
Coding: c.412C>T
MANE Select: NM_000423
dbSNP: rs1279729635
Type: single nucleotide variant
Location: chr12:52651731 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.38
Residue 138: the 'head' region

Full KRT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT2 p.Pro138= Likely benign ★ same residue
KRT2 p.Glu487Lys Pathogenic ★★ same type
KRT2 p.Glu488Lys Likely pathogenic ★★ same type
KRT2 p.Arg544Gln Uncertain significance ★★ ⚠ same type
KRT2 p.Asn498Ile Uncertain significance ★★ ⚠ same type
KRT2 c.1122+16G>A Benign ★★ same type
KRT2 c.1248+22C>T Benign ★★ same type
KRT2 c.1249-4A>G Benign ★★ 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/krt2-p-pro138ser (accessed [today's date]).

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