Is KRT6C p.Ser41Pro (c.121T>C) pathogenic?

KRT6C p.Ser41Pro (c.121T>C) is classified Uncertain significance in KRT6C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.1433); Ultra-rare (popmax 0.033%, sas); Associated with Inborn genetic diseases.

What condition is associated with KRT6C p.Ser41Pro (c.121T>C)?

KRT6C p.Ser41Pro (c.121T>C) is associated with Inborn genetic diseases (ClinVar).

How common is KRT6C p.Ser41Pro (c.121T>C) in the general population?

KRT6C p.Ser41Pro (c.121T>C) is ultra-rare (popmax 0.033%, sas) (gnomAD).

What do computational predictors say about KRT6C p.Ser41Pro (c.121T>C)?

AlphaMissense predicts likely benign (score 0.1433) — an in-silico prediction, not a clinical call.

KRT6C p.Ser41Pro

c.121T>C · VCV4045078

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1433 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1433	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -8.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -10	GERP 0.73
Regional constraint	o/e 0.71	unconstrained · MANE · 226 bp · p 0.0039 · regional, not allelic
Overall
CADD	22.6	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 0.033% South Asian · 30/90,818 alleles

Filtering AF 0.0238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0206%

Overall 0.00249% 40/1,609,268 alleles · ultra-rare exomes 39/1,458,868 · genomes 1/150,400 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.033%	3,027
Remaining individualsnot grpmax-eligible	0.00803%	12,453
Admixed American	0.00168%	59,412
European (non-Finnish)	0.000339%	294,746

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: KRT6C
Protein: p.Ser41Pro
Coding: c.121T>C
MANE Select: NM_173086
Type: single nucleotide variant
Location: chr12:52473617 (GRCh38)
Gene constraint: LOEUF 1.34 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.63
Residue 41: the 'head' region

Full KRT6C 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

KRT6C p.Arg260Cys Uncertain significance ★★ ⚠ same condition
KRT6C p.Arg349Trp Uncertain significance ★★ ⚠ same condition
KRT6C p.Arg466Cys Uncertain significance ★★ ⚠ same condition
KRT6C p.Asp331His Uncertain significance ★★ ⚠ same condition
KRT6C p.Glu479Lys Uncertain significance ★★ same condition
KRT6C p.Gly504Ser Uncertain significance ★★ ⚠ same condition
KRT6C p.Gly525Ser Uncertain significance ★★ ⚠ same condition
KRT6C p.Gly57Arg 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/krt6c-p-ser41pro (accessed [today's date]).

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