Is LORICRIN p.Pro12Ser (c.34C>T) pathogenic?

LORICRIN p.Pro12Ser (c.34C>T) is classified Uncertain significance in LORICRIN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-07). AlphaMissense: likely pathogenic (0.7356); No allele count reported in gnomAD v4.1 (AN 1,594,832); Associated with loricrin keratoderma.

What condition is associated with LORICRIN p.Pro12Ser (c.34C>T)?

LORICRIN p.Pro12Ser (c.34C>T) is associated with loricrin keratoderma (ClinVar).

How common is LORICRIN p.Pro12Ser (c.34C>T) in the general population?

LORICRIN p.Pro12Ser (c.34C>T) is no allele count reported in gnomAD v4.1 (AN 1,594,832) (gnomAD).

What do computational predictors say about LORICRIN p.Pro12Ser (c.34C>T)?

AlphaMissense predicts likely pathogenic (score 0.7356) — an in-silico prediction, not a clinical call.

LORICRIN p.Pro12Ser

Q: How is Keratoderma hereditarium mutilans with ichthyosis inherited?

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

c.34C>T · VCV3779817

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7356 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,594,832)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

loricrin keratoderma

Computational evidence

Protein change
AlphaMissense	0.7356	likely pathogenic · top 7% in LORICRIN
REVEL	0.141	moderately benign-leaning
SaProt	LLR -7.38	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -0.63, phastCons 0.41
Regional constraint	o/e 1.14	unconstrained · MANE · 935 bp · p 0.003 · regional, not allelic
Overall
CADD	18.12	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

No allele count reported in gnomAD v4.1 (AN 1,594,832). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: LORICRIN
Protein: p.Pro12Ser
Coding: c.34C>T
MANE Select: NM_000427
Type: single nucleotide variant
Location: chr1:153260983 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.91
Residue 12: the 'disordered' region

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.Pro12Thr Uncertain significance ★ ⚠ same residue
LORICRIN p.Ser91Phe Benign/Likely benign ★★ same condition
LORICRIN p.Gly162Ter Likely pathogenic ★ same condition
LORICRIN p.Tyr208Ter Likely pathogenic ★ same condition
LORICRIN p.Gly246Arg Uncertain significance ★ ⚠ same condition
LORICRIN p.Ser229fs Pathogenic ★★ same condition
LORICRIN p.Gly173fs Pathogenic ★ same condition
LORICRIN p.Gly41dup Conflicting classifications of pathogenicity ★ 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-pro12ser (accessed [today's date]).

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