Is LORICRIN p.Ser256Phe (c.767C>T) pathogenic?

LORICRIN p.Ser256Phe (c.767C>T) is classified Uncertain significance in LORICRIN (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-28). AlphaMissense: likely benign (0.2076); Very rare (popmax 0.00421%, afr).

How common is LORICRIN p.Ser256Phe (c.767C>T) in the general population?

LORICRIN p.Ser256Phe (c.767C>T) is very rare (popmax 0.00421%, afr) (gnomAD).

What do computational predictors say about LORICRIN p.Ser256Phe (c.767C>T)?

AlphaMissense predicts likely benign (score 0.2076) — an in-silico prediction, not a clinical call.

LORICRIN p.Ser256Phe

c.767C>T · VCV4703154

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2076 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00421%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2076	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -11.29	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4	GERP 1.4
Regional constraint	o/e 1.14	unconstrained · MANE · 935 bp · p 0.003 · regional, not allelic
Overall
CADD	8.016	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 0.00421% African / African-American · 3/71,300 alleles

Filtering AF 0.00112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00061%

Overall 0.000257% 4/1,554,288 alleles · very rare exomes 4/1,403,312 · genomes 0/150,976 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00421%	23,767
European (non-Finnish)	8.63e-05%	1,159,393

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.Ser256Phe
Coding: c.767C>T
MANE Select: NM_000427
Type: single nucleotide variant
Location: chr1:153261716 (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

Similar variants

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
LORICRIN p.Ser169Phe Benign/Likely 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-ser256phe (accessed [today's date]).

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