Is KRT4 p.Ala72Val (c.215C>T) pathogenic?

KRT4 p.Ala72Val (c.215C>T) is classified Benign in KRT4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-05-04). AlphaMissense: likely benign (0.0949); Common (popmax 60.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with white sponge nevus 1.

What condition is associated with KRT4 p.Ala72Val (c.215C>T)?

KRT4 p.Ala72Val (c.215C>T) is associated with white sponge nevus 1 (ClinVar).

How is White sponge nevus inherited?

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

What do computational predictors say about KRT4 p.Ala72Val (c.215C>T)?

AlphaMissense predicts likely benign (score 0.0949) — an in-silico prediction, not a clinical call.

KRT4 p.Ala72Val

Q: How common is KRT4 p.Ala72Val (c.215C>T) in the general population?

KRT4 p.Ala72Val (c.215C>T) is common (popmax 60.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.215C>T · rs2638525 · VCV309709

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0949 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 60.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

white sponge nevus 1

Computational evidence

Protein change
AlphaMissense	0.0949	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -7.17	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 2.6	GERP -2.4, phastCons 0.21
Regional constraint	o/e 1.01	unconstrained · MANE · 6,986 bp · p 0.83 · regional, not allelic
Overall
CADD	16.35	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 60.3% African / African-American · 31,063/51,544 alleles

Filtering AF 59.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 59.5%

Overall 40.2% 292,610/728,388 alleles · common exomes 257,138/663,838 · genomes 35,472/64,550 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	60.3%	2
Amishnot grpmax-eligible	54.3%	2
European (non-Finnish)	40.6%	2
Remaining individualsnot grpmax-eligible	39.6%	3
Ashkenazi Jewishnot grpmax-eligible	37.5%	3
Finnishnot grpmax-eligible	36%	3
South Asian	31.1%	3
Middle Eastern	30.4%	3
Admixed American	26.5%	4
East Asian	19.1%	5

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: KRT4
Protein: p.Ala72Val
Coding: c.215C>T
MANE Select: NM_002272
dbSNP: rs2638525
Type: single nucleotide variant
Location: chr12:52813844 (GRCh38)
Gene constraint: LOEUF 1.089 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.77
Residue 72: a UniProt-annotated variant site (in allele k4a1); the 'head' region

Full KRT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

white sponge nevus 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For White sponge nevus (Orphanet):

Inheritance: Autosomal dominant

Similar variants

KRT4 p.Ala106Gly Uncertain significance ★★ ⚠ same condition
KRT4 p.Asp153Asn Uncertain significance ★★ ⚠ same condition
KRT4 p.Asp247Glu Uncertain significance ★★ same condition
KRT4 c.1346+15A>G Benign ★★ same condition
KRT4 c.1346+15A>T Likely benign ★★ same condition
KRT4 c.1381+15C>T Benign ★★ same condition
KRT4 c.678-14G>A Benign ★★ same condition
KRT4 c.678-3C>T 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/krt4-p-ala72val (accessed [today's date]).

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