Is POMP p.Leu31Phe (c.91C>T) pathogenic?

POMP p.Leu31Phe (c.91C>T) is classified Uncertain significance in POMP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-09). AlphaMissense: likely benign (0.1457); Ultra-rare (popmax 0.0574%, afr); Associated with keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome.

How common is POMP p.Leu31Phe (c.91C>T) in the general population?

POMP p.Leu31Phe (c.91C>T) is ultra-rare (popmax 0.0574%, afr) (gnomAD).

What do computational predictors say about POMP p.Leu31Phe (c.91C>T)?

AlphaMissense predicts likely benign (score 0.1457) — an in-silico prediction, not a clinical call.

POMP p.Leu31Phe

Q: What condition is associated with POMP p.Leu31Phe (c.91C>T)?

POMP p.Leu31Phe (c.91C>T) is associated with keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome, proteasome-associated autoinflammatory syndrome 2 (ClinVar).

Q: How is Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome inherited?

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

c.91C>T · rs138472024 · VCV1492095

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1457 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0574%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome

Computational evidence

Protein change
AlphaMissense	0.1457	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.24	loss · gain 0.02 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 19 kb · p 0.048 · regional, not allelic
Overall
CADD	25.3	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 0.0574% African / African-American · 43/74,946 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.039%

Overall 0.00354% 57/1,610,534 alleles · ultra-rare exomes 19/1,458,250 · genomes 38/152,284 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0574%	1,743
Admixed American	0.02%	5,002
Remaining individualsnot grpmax-eligible	0.0032%	31,203

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: POMP
Protein: p.Leu31Phe
Coding: c.91C>T
MANE Select: NM_015932
dbSNP: rs138472024
Type: single nucleotide variant
Location: chr13:28662497 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 81.76 · 11 PDB
Residue 31: a turn

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

Disease context

keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: proteasome-associated autoinflammatory syndrome 2

For Keratosis linearis-ichthyosis congenita-sclerosing keratoderma syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

POMP c.101+9G>A Benign/Likely benign ★★ same condition
POMP c.265-1G>C Conflicting classifications of pathogenicity ★ same condition
POMP p.Leu31del Uncertain significance ★ same residue
POMP p.Ile112fs Pathogenic ★★ same condition
POMP p.Glu115fs Pathogenic same condition
POMP p.Phe114fs Pathogenic same condition
POMP p.Arg32Gln Uncertain significance ★★ ⚠ same type
POMP p.Arg32Trp Uncertain significance ★★ ⚠ 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/pomp-p-leu31phe (accessed [today's date]).

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