Is KRT5 p.Arg395Ser (c.1185G>C) pathogenic?

KRT5 p.Arg395Ser (c.1185G>C) is classified Uncertain significance in KRT5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely pathogenic (0.9956); Very rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with KRT5 p.Arg395Ser (c.1185G>C)?

KRT5 p.Arg395Ser (c.1185G>C) is associated with Inborn genetic diseases (ClinVar).

How common is KRT5 p.Arg395Ser (c.1185G>C) in the general population?

KRT5 p.Arg395Ser (c.1185G>C) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about KRT5 p.Arg395Ser (c.1185G>C)?

AlphaMissense predicts likely pathogenic (score 0.9956) — an in-silico prediction, not a clinical call.

KRT5 p.Arg395Ser

c.1185G>C · VCV3536084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9956 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9956	likely pathogenic · top 6% in KRT5
REVEL	0.666	pathogenic-leaning
SaProt	LLR -14.36	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.019	phastCons 0.79
Regional constraint	o/e 0.98	unconstrained · MANE · 2,753 bp · p 0.69 · regional, not allelic
Overall
CADD	22.7	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 0.01% Admixed American · 6/60,022 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000372% 6/1,614,180 alleles · very rare exomes 6/1,461,880 · genomes 0/152,300 · 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: KRT5
Protein: p.Arg395Ser
Coding: c.1185G>C
MANE Select: NM_000424
Type: single nucleotide variant
Location: chr12:52517140 (GRCh38)
Gene constraint: LOEUF 0.538 · pLI 0.90 (gnomAD)
Structure: AlphaFold pLDDT 68.86 · 2 PDB
Residue 395: the if rod domain; an α-helix; a UniProt-annotated variant site (in ddd1); the 'coil 2' region

Full KRT5 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

KRT5 p.Pro25Leu Pathogenic ★★ same condition
KRT5 p.Ala101Thr Uncertain significance ★★ ⚠ same condition
KRT5 p.Ala20Thr Uncertain significance ★★ ⚠ same condition
KRT5 p.Arg169His Uncertain significance ★★ ⚠ same condition
KRT5 p.Arg239Cys Uncertain significance ★★ ⚠ same condition
KRT5 p.Arg354Trp Uncertain significance ★★ ⚠ same condition
KRT5 p.Arg559Gln Uncertain significance ★★ ⚠ same condition
KRT5 p.Arg585Trp 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/krt5-p-arg395ser (accessed [today's date]).

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