Is KRT9 p.Ser438Arg (c.1312A>C) pathogenic?

KRT9 p.Ser438Arg (c.1312A>C) is classified Uncertain significance in KRT9 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-15). AlphaMissense: ambiguous (0.4701); Ultra-rare (popmax 0.0142%, nfe); Associated with Inborn genetic diseases.

What condition is associated with KRT9 p.Ser438Arg (c.1312A>C)?

KRT9 p.Ser438Arg (c.1312A>C) is associated with Inborn genetic diseases (ClinVar).

How common is KRT9 p.Ser438Arg (c.1312A>C) in the general population?

KRT9 p.Ser438Arg (c.1312A>C) is ultra-rare (popmax 0.0142%, nfe) (gnomAD).

What do computational predictors say about KRT9 p.Ser438Arg (c.1312A>C)?

AlphaMissense predicts ambiguous (score 0.4701) — an in-silico prediction, not a clinical call.

KRT9 p.Ser438Arg

c.1312A>C · rs201887979 · VCV2411040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4701 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0142%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4701	ambiguous
REVEL	0.268	benign-leaning
SaProt	LLR -6.55	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.56	GERP -2.4
Regional constraint	o/e 0.90	unconstrained · MANE · 4,200 bp · p 0.017 · regional, not allelic
Overall
CADD	15.72	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0142% European (non-Finnish) · 167/1,180,024 alleles

Filtering AF 0.0124% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0117%

Overall 0.0108% 174/1,614,034 alleles · ultra-rare exomes 170/1,461,880 · genomes 4/152,154 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0142%	7,066
Remaining individualsnot grpmax-eligible	0.008%	12,497
African / African-American	0.00267%	37,461

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: KRT9
Protein: p.Ser438Arg
Coding: c.1312A>C
MANE Select: NM_000226
dbSNP: rs201887979
Type: single nucleotide variant
Location: chr17:41568244 (GRCh38)
Gene constraint: LOEUF 0.873 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.43
Residue 438: the if rod domain; the 'coil 2' region

Full KRT9 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

KRT9 p.Arg13His Uncertain significance ★★ ⚠ same condition
KRT9 p.Gly116Asp Uncertain significance ★★ ⚠ same condition
KRT9 p.Gly193Glu Uncertain significance ★★ ⚠ same condition
KRT9 p.Gly507Arg Uncertain significance ★★ same condition
KRT9 p.Gly507Val Uncertain significance ★★ ⚠ same condition
KRT9 p.Ile341Val Uncertain significance ★★ ⚠ same condition
KRT9 p.Ser357Pro Uncertain significance ★★ ⚠ same condition
KRT9 p.Ser8Leu 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/krt9-p-ser438arg (accessed [today's date]).

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