Is KRT6A p.Ser561Arg (c.1683C>A) pathogenic?

KRT6A p.Ser561Arg (c.1683C>A) is classified Uncertain significance in KRT6A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-25). AlphaMissense: likely pathogenic (0.6932); Very rare (popmax 0.00144%, nfe).

How common is KRT6A p.Ser561Arg (c.1683C>A) in the general population?

KRT6A p.Ser561Arg (c.1683C>A) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about KRT6A p.Ser561Arg (c.1683C>A)?

AlphaMissense predicts likely pathogenic (score 0.6932) — an in-silico prediction, not a clinical call.

KRT6A p.Ser561Arg

c.1683C>A · rs1592183684 · VCV2854670

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6932 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6932	likely pathogenic
REVEL	0.347	indeterminate
SaProt	LLR -9.93	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.31	GERP 1.9
Regional constraint	o/e 1.00	unconstrained · MANE · 5,122 bp · p 0.98 · regional, not allelic
Overall
CADD	22.3	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 0.00144% European (non-Finnish) · 17/1,180,034 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00105% 17/1,614,196 alleles · very rare exomes 17/1,461,880 · genomes 0/152,316 · 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: KRT6A
Protein: p.Ser561Arg
Coding: c.1683C>A
MANE Select: NM_005554
dbSNP: rs1592183684
Type: single nucleotide variant
Location: chr12:52487732 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.16 · 1 PDB
Residue 561: the 'tail' region

Full KRT6A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KRT6A c.1460-1G>C Pathogenic/Likely pathogenic ★★ same type
KRT6A p.Arg164Cys Pathogenic/Likely pathogenic ★★ same type
KRT6A p.Asn171Lys Pathogenic ★★ same type
KRT6A p.Asn171Ser Pathogenic ★★ same type
KRT6A p.Glu163Lys Pathogenic ★★ same type
KRT6A p.Glu472Lys Pathogenic/Likely pathogenic ★★ same type
KRT6A p.Ile462Asn Pathogenic/Likely pathogenic ★★ same type
KRT6A p.Leu170Phe Pathogenic ★★ 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/krt6a-p-ser561arg (accessed [today's date]).

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