Is KRT6C p.Ser404Arg (c.1212C>G) pathogenic?

KRT6C p.Ser404Arg (c.1212C>G) is classified Uncertain significance in KRT6C (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-07). AlphaMissense: likely pathogenic (0.6829); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KRT6C p.Ser404Arg (c.1212C>G)?

KRT6C p.Ser404Arg (c.1212C>G) is associated with Inborn genetic diseases (ClinVar).

How common is KRT6C p.Ser404Arg (c.1212C>G) in the general population?

KRT6C p.Ser404Arg (c.1212C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about KRT6C p.Ser404Arg (c.1212C>G)?

AlphaMissense predicts likely pathogenic (score 0.6829) — an in-silico prediction, not a clinical call.

KRT6C p.Ser404Arg

c.1212C>G · VCV4045081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6829 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6829	likely pathogenic
REVEL	0.355	indeterminate
SaProt	LLR -12.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -1.6
Regional constraint	o/e 0.97	unconstrained · MANE · 3,104 bp · p 0.49 · regional, not allelic
Overall
CADD	17.46	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000339% European (non-Finnish) · 4/1,180,026 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,018 alleles · very rare exomes 3/1,461,864 · genomes 1/152,154 · joint denominator

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.Ser404Arg
Coding: c.1212C>G
MANE Select: NM_173086
Type: single nucleotide variant
Location: chr12:52469882 (GRCh38)
Gene constraint: LOEUF 1.34 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.63
Residue 404: the if rod domain; the 'coil 2' 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-ser404arg (accessed [today's date]).

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