Is KRT83 p.Pro475Ser (c.1423C>T) pathogenic?

KRT83 p.Pro475Ser (c.1423C>T) is classified Conflicting classifications of pathogenicity in KRT83 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-26). AlphaMissense: likely benign (0.1001); Ultra-rare (popmax 0.0523%, afr); Associated with monilethrix.

What condition is associated with KRT83 p.Pro475Ser (c.1423C>T)?

KRT83 p.Pro475Ser (c.1423C>T) is associated with monilethrix (ClinVar).

How common is KRT83 p.Pro475Ser (c.1423C>T) in the general population?

KRT83 p.Pro475Ser (c.1423C>T) is ultra-rare (popmax 0.0523%, afr) (gnomAD).

How is Monilethrix inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about KRT83 p.Pro475Ser (c.1423C>T)?

AlphaMissense predicts likely benign (score 0.1001) — an in-silico prediction, not a clinical call.

KRT83 p.Pro475Ser

c.1423C>T · rs200232339 · VCV309495

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1001 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0523%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

monilethrix

Computational evidence

Protein change
AlphaMissense	0.1001	likely benign
REVEL	0.438	indeterminate
SaProt	LLR -6.04	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 0.68, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 6,701 bp · p 0.63 · regional, not allelic
Overall
CADD	19.3	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 0.0523% African / African-American · 39/74,638 alleles

Filtering AF 0.0393% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0347%

Overall 0.00391% 62/1,583,906 alleles · ultra-rare exomes 48/1,431,566 · genomes 14/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0523%	1,914
Middle Eastern	0.039%	2,561
Admixed American	0.00358%	27,898
Remaining individualsnot grpmax-eligible	0.00163%	61,314
European (non-Finnish)	0.00154%	64,730

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: KRT83
Protein: p.Pro475Ser
Coding: c.1423C>T
MANE Select: NM_002282
dbSNP: rs200232339
Type: single nucleotide variant
Location: chr12:52314690 (GRCh38)
Gene constraint: LOEUF 1.226 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.81
Residue 475: the 'tail' region

Full KRT83 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

monilethrix — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Monilethrix (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

KRT83 p.Pro475= Uncertain significance ★ same residue
KRT83 p.Glu407Lys Likely pathogenic ★★ same condition
KRT83 p.Arg168Trp Uncertain significance ★★ ⚠ same condition
KRT83 p.Arg272Gln Uncertain significance ★★ ⚠ same condition
KRT83 p.Glu172Lys Uncertain significance ★★ ⚠ same condition
KRT83 c.1041+6A>G Benign ★★ same condition
KRT83 c.1042-4C>A Benign ★★ same condition
KRT83 c.750+15A>G Benign ★★ 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/krt83-p-pro475ser (accessed [today's date]).

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