Is KRT16 p.Ala415Val (c.1244C>T) pathogenic?

KRT16 p.Ala415Val (c.1244C>T) is classified Uncertain significance in KRT16 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). AlphaMissense: ambiguous (0.5158); Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with KRT16 p.Ala415Val (c.1244C>T)?

KRT16 p.Ala415Val (c.1244C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KRT16 p.Ala415Val (c.1244C>T) in the general population?

KRT16 p.Ala415Val (c.1244C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about KRT16 p.Ala415Val (c.1244C>T)?

AlphaMissense predicts ambiguous (score 0.5158) — an in-silico prediction, not a clinical call.

KRT16 p.Ala415Val

c.1244C>T · VCV3535853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5158 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5158	ambiguous
REVEL	0.673	pathogenic-leaning
SaProt	LLR -9.84	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.7	GERP 0.74, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 2,750 bp · p 0.0085 · regional, not allelic
Overall
CADD	28.7	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 0.0107% African / African-American · 8/74,872 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000496% 8/1,612,438 alleles · ultra-rare exomes 3/1,460,214 · genomes 5/152,224 · 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: KRT16
Protein: p.Ala415Val
Coding: c.1244C>T
MANE Select: NM_005557
Type: single nucleotide variant
Location: chr17:41610367 (GRCh38)
Gene constraint: LOEUF 1.178 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.26
Residue 415: the if rod domain; the 'coil 2' region

Full KRT16 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

KRT16 p.Arg290His Uncertain significance ★★ ⚠ same condition
KRT16 p.Glu442Lys Uncertain significance ★★ ⚠ same condition
KRT16 p.Trp152Ser Uncertain significance ★★ ⚠ same condition
KRT16 p.Ala355Ser Uncertain significance ★ ⚠ same condition
KRT16 p.Ala42Val Uncertain significance ★ ⚠ same condition
KRT16 p.Ala433Thr Uncertain significance ★ ⚠ same condition
KRT16 p.Ala61Val Uncertain significance ★ ⚠ same condition
KRT16 p.Arg136His 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/krt16-p-ala415val (accessed [today's date]).

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