Is LORICRIN p.Ser91Phe (c.272C>T) pathogenic?

LORICRIN p.Ser91Phe (c.272C>T) is classified Benign/Likely benign in LORICRIN (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.2468); Low-frequency (popmax 2.51%, mid); Associated with loricrin keratoderma.

What condition is associated with LORICRIN p.Ser91Phe (c.272C>T)?

LORICRIN p.Ser91Phe (c.272C>T) is associated with loricrin keratoderma (ClinVar).

How common is LORICRIN p.Ser91Phe (c.272C>T) in the general population?

LORICRIN p.Ser91Phe (c.272C>T) is low-frequency (popmax 2.51%, mid) (gnomAD).

What do computational predictors say about LORICRIN p.Ser91Phe (c.272C>T)?

AlphaMissense predicts likely benign (score 0.2468) — an in-silico prediction, not a clinical call.

LORICRIN p.Ser91Phe

Q: How is Keratoderma hereditarium mutilans with ichthyosis inherited?

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

c.272C>T · rs533773105 · VCV2035667

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2468 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.51%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

loricrin keratoderma

Computational evidence

Protein change
AlphaMissense	0.2468	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -9.77	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 -3.4	GERP -1.9
Regional constraint	o/e 1.14	unconstrained · MANE · 935 bp · p 0.003 · regional, not allelic
Overall
CADD	13.36	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 2.51% Middle Eastern · 102/4,056 alleles

Filtering AF 2.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.97%

Overall 0.326% 4,434/1,359,422 alleles · low-frequency exomes 4,093/1,219,414 · genomes 341/140,008 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	2.51%	40
Ashkenazi Jewishnot grpmax-eligible	0.511%	196
Remaining individualsnot grpmax-eligible	0.498%	201
Admixed American	0.371%	269
South Asian	0.339%	295
European (non-Finnish)	0.338%	295
African / African-American	0.0793%	1,261
Finnishnot grpmax-eligible	0.0431%	2,318
East Asian	0.0123%	8,137

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: LORICRIN
Protein: p.Ser91Phe
Coding: c.272C>T
MANE Select: NM_000427
dbSNP: rs533773105
Type: single nucleotide variant
Location: chr1:153261221 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.91

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

Disease context

loricrin keratoderma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Keratoderma hereditarium mutilans with ichthyosis (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

LORICRIN p.Ser91Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
LORICRIN p.Ser91Thr Uncertain significance ★ ⚠ same residue
LORICRIN p.Gly162Ter Likely pathogenic ★ same condition
LORICRIN p.Tyr208Ter Likely pathogenic ★ same condition
LORICRIN p.Gly246Arg Uncertain significance ★ ⚠ same condition
LORICRIN p.Pro12Ser Uncertain significance ★ ⚠ same condition
LORICRIN p.Ser229fs Pathogenic ★★ same condition
LORICRIN p.Gly173fs Pathogenic ★ 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/loricrin-p-ser91phe (accessed [today's date]).

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