Is KRT6C p.Val486Ile (c.1456G>A) pathogenic?

KRT6C p.Val486Ile (c.1456G>A) is classified Benign/Likely benign in KRT6C (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-23). AlphaMissense: likely benign (0.0597); Rare (popmax 0.168%, afr); Associated with Inborn genetic diseases.

What condition is associated with KRT6C p.Val486Ile (c.1456G>A)?

KRT6C p.Val486Ile (c.1456G>A) is associated with Inborn genetic diseases (ClinVar).

How common is KRT6C p.Val486Ile (c.1456G>A) in the general population?

KRT6C p.Val486Ile (c.1456G>A) is rare (popmax 0.168%, afr) (gnomAD).

What do computational predictors say about KRT6C p.Val486Ile (c.1456G>A)?

AlphaMissense predicts likely benign (score 0.0597) — an in-silico prediction, not a clinical call.

KRT6C p.Val486Ile

c.1456G>A · rs11540298 · VCV2701612

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0597 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.168%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0597	likely benign
REVEL	0.151	moderately benign-leaning
SaProt	LLR -7.73	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 0.73	GERP 0.73, phastCons 0.77
Regional constraint	o/e 0.97	unconstrained · MANE · 3,104 bp · p 0.49 · regional, not allelic
Overall
CADD	14.88	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 0.168% African / African-American · 126/75,024 alleles

Filtering AF 0.144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.135%

Overall 0.0284% 458/1,613,908 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.168%	595
Remaining individualsnot grpmax-eligible	0.032%	3,125
Finnishnot grpmax-eligible	0.0234%	4,269
European (non-Finnish)	0.0225%	4,435
South Asian	0.022%	4,553
East Asian	0.0156%	6,410
Admixed American	0.00666%	15,004

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: KRT6C
Protein: p.Val486Ile
Coding: c.1456G>A
MANE Select: NM_173086
dbSNP: rs11540298
Type: single nucleotide variant
Location: chr12:52469414 (GRCh38)
Gene constraint: LOEUF 1.34 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.63
Residue 486: the 'tail' region

Full KRT6C 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

KRT6C p.Arg260Cys Uncertain significance ★★ ⚠ same condition
KRT6C p.Arg349Trp Uncertain significance ★★ ⚠ same condition
KRT6C p.Arg466Cys Uncertain significance ★★ ⚠ same condition
KRT6C p.Asp331His Uncertain significance ★★ ⚠ same condition
KRT6C p.Glu479Lys Uncertain significance ★★ same condition
KRT6C p.Gly504Ser Uncertain significance ★★ ⚠ same condition
KRT6C p.Gly525Ser Uncertain significance ★★ ⚠ same condition
KRT6C p.Gly57Arg 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/krt6c-p-val486ile (accessed [today's date]).

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