Is KRT8 p.Ser445Cys (c.1334C>G) pathogenic?

KRT8 p.Ser445Cys (c.1334C>G) is classified Uncertain significance in KRT8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-14). AlphaMissense: likely benign (0.1028); Ultra-rare (popmax 0.0179%, nfe).

How common is KRT8 p.Ser445Cys (c.1334C>G) in the general population?

KRT8 p.Ser445Cys (c.1334C>G) is ultra-rare (popmax 0.0179%, nfe) (gnomAD).

What do computational predictors say about KRT8 p.Ser445Cys (c.1334C>G)?

AlphaMissense predicts likely benign (score 0.1028) — an in-silico prediction, not a clinical call.

KRT8 p.Ser445Cys

c.1334C>G · rs748771942 · VCV2396856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1028 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1028	likely benign
REVEL	0.335	indeterminate
SaProt	LLR -11.27	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.80	unconstrained · MANE · 4,614 bp · p 1.2e-05 · regional, not allelic
Overall
CADD	22.7	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 0.0179% European (non-Finnish) · 210/1,174,054 alleles

Filtering AF 0.0159% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.0134% 214/1,591,712 alleles · ultra-rare exomes 205/1,439,474 · genomes 9/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0179%	5,591
Remaining individualsnot grpmax-eligible	0.00484%	20,675
African / African-American	0.00134%	74,746

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: KRT8
Protein: p.Ser445Cys
Coding: c.1334C>G
MANE Select: NM_002273
dbSNP: rs748771942
Type: single nucleotide variant
Location: chr12:52897546 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.13 · 3 PDB
Residue 445: the 'tail' region

Full KRT8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT8 p.Lys464Asn Uncertain significance ★★ ⚠ same type
KRT8 c.-4T>C Benign ★★ same type
KRT8 p.Ala333= Benign ★★ same type
KRT8 p.Arg341His Benign ★★ same type
KRT8 p.Gly434Ser Benign ★★ same type
KRT8 p.Gly62Cys Benign/Likely benign ★★ ⚠ same type
KRT8 p.Ile63Val Benign/Likely benign ★★ ⚠ same type
KRT8 p.Tyr54His Benign/Likely 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/krt8-p-ser445cys (accessed [today's date]).

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