Is LORICRIN p.Gly287Cys (c.859G>T) pathogenic?

LORICRIN p.Gly287Cys (c.859G>T) is classified Uncertain significance in LORICRIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-15). AlphaMissense: likely benign (0.2014); Very rare (popmax 0.00534%, afr).

How common is LORICRIN p.Gly287Cys (c.859G>T) in the general population?

LORICRIN p.Gly287Cys (c.859G>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about LORICRIN p.Gly287Cys (c.859G>T)?

AlphaMissense predicts likely benign (score 0.2014) — an in-silico prediction, not a clinical call.

LORICRIN p.Gly287Cys

c.859G>T · VCV4048000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2014 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2014	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -6.34	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 -0.22, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 935 bp · p 0.003 · regional, not allelic
Overall
CADD	22.5	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 0.00534% African / African-American · 4/74,868 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000249% 4/1,609,392 alleles · very rare exomes 1/1,457,270 · genomes 3/152,122 · 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: LORICRIN
Protein: p.Gly287Cys
Coding: c.859G>T
MANE Select: NM_000427
Type: single nucleotide variant
Location: chr1:153261808 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.91
Residue 287: the 'disordered' region

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

Similar variants

LORICRIN p.Gly287Asp Uncertain significance ★ ⚠ same residue
LORICRIN p.Ser115Phe Uncertain significance ★★ ⚠ same type
LORICRIN p.Ser243Thr Uncertain significance ★★ ⚠ same type
LORICRIN p.Thr19Ala Uncertain significance ★★ ⚠ same type
LORICRIN p.Cys51= Benign ★★ same type
LORICRIN p.Gly108Ala Benign/Likely benign ★★ ⚠ same type
LORICRIN p.Gly290= Benign ★★ same type
LORICRIN p.Gly92= Benign ★★ 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/loricrin-p-gly287cys (accessed [today's date]).

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