Is KRT6A p.Phe122Ser (c.365T>C) pathogenic?

KRT6A p.Phe122Ser (c.365T>C) is classified Uncertain significance in KRT6A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely benign (0.2048); Rare (popmax 0.316%, sas); Associated with Inborn genetic diseases.

What condition is associated with KRT6A p.Phe122Ser (c.365T>C)?

KRT6A p.Phe122Ser (c.365T>C) is associated with Inborn genetic diseases (ClinVar).

How common is KRT6A p.Phe122Ser (c.365T>C) in the general population?

KRT6A p.Phe122Ser (c.365T>C) is rare (popmax 0.316%, sas) (gnomAD).

What do computational predictors say about KRT6A p.Phe122Ser (c.365T>C)?

AlphaMissense predicts likely benign (score 0.2048) — an in-silico prediction, not a clinical call.

KRT6A p.Phe122Ser

c.365T>C · rs549671322 · VCV2523517

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2048 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.316%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2048	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -2.1
Regional constraint	o/e 1.00	unconstrained · MANE · 5,122 bp · p 0.98 · regional, not allelic
Overall
CADD	8.717	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.316% South Asian · 287/90,898 alleles

Filtering AF 0.286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.274%

Overall 0.0187% 301/1,612,240 alleles · rare exomes 291/1,460,770 · genomes 10/151,470 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.316%	317
Middle Eastern	0.0179%	5,586
Remaining individualsnot grpmax-eligible	0.0128%	7,800
African / African-American	0.00268%	37,379
European (non-Finnish)	0.000254%	393,137

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.Phe122Ser
Coding: c.365T>C
MANE Select: NM_005554
dbSNP: rs549671322
Type: single nucleotide variant
Location: chr12:52492824 (GRCh38)
Gene constraint: LOEUF 0.755 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.16 · 1 PDB
Residue 122: the 'head' region

Full KRT6A 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

KRT6A p.Ala403Thr Uncertain significance ★★ ⚠ same condition
KRT6A p.Arg16Trp Uncertain significance ★★ ⚠ same condition
KRT6A p.Arg240Gly Uncertain significance ★★ same condition
KRT6A p.Gly202Ser Uncertain significance ★★ ⚠ same condition
KRT6A p.Gly510Asp Uncertain significance ★★ same condition
KRT6A p.Lys400Gln Uncertain significance ★★ ⚠ same condition
KRT6A p.Val282Phe Uncertain significance ★★ ⚠ same condition
KRT6A p.Val481Ile 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/krt6a-p-phe122ser (accessed [today's date]).

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