Is LORICRIN p.Ser145Phe (c.434C>T) pathogenic?

LORICRIN p.Ser145Phe (c.434C>T) is classified Likely benign in LORICRIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: ambiguous (0.3474); Very rare (popmax 0.00165%, afr).

How common is LORICRIN p.Ser145Phe (c.434C>T) in the general population?

LORICRIN p.Ser145Phe (c.434C>T) is very rare (popmax 0.00165%, afr) (gnomAD).

What do computational predictors say about LORICRIN p.Ser145Phe (c.434C>T)?

AlphaMissense predicts ambiguous (score 0.3474) — an in-silico prediction, not a clinical call.

LORICRIN p.Ser145Phe

c.434C>T · VCV4098947

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3474 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00165%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3474	ambiguous
REVEL	0.174	moderately benign-leaning
SaProt	LLR -12.78	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Regional constraint	o/e 1.14	unconstrained · MANE · 935 bp · p 0.003 · regional, not allelic
Overall
CADD	13.69	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 0.00165% African / African-American · 1/60,780 alleles

Filtering AF 0.000808% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000641%

Overall 0.00116% 17/1,461,718 alleles · very rare exomes 15/1,332,964 · genomes 2/128,754 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00165%	60,780
European (non-Finnish)	0.00135%	74,328
South Asian	0.00128%	78,034

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.Ser145Phe
Coding: c.434C>T
MANE Select: NM_000427
Type: single nucleotide variant
Location: chr1:153261383 (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-ser145phe (accessed [today's date]).

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