Is LORICRIN p.Ser174Pro (c.520T>C) pathogenic?

LORICRIN p.Ser174Pro (c.520T>C) is classified Uncertain significance in LORICRIN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). AlphaMissense: ambiguous (0.3476); Very rare (popmax 0.00647%, amr).

How common is LORICRIN p.Ser174Pro (c.520T>C) in the general population?

LORICRIN p.Ser174Pro (c.520T>C) is very rare (popmax 0.00647%, amr) (gnomAD).

What do computational predictors say about LORICRIN p.Ser174Pro (c.520T>C)?

AlphaMissense predicts ambiguous (score 0.3476) — an in-silico prediction, not a clinical call.

LORICRIN p.Ser174Pro

c.520T>C · VCV4098946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3476 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00647%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3476	ambiguous
REVEL	0.096	moderately benign-leaning
SaProt	LLR -12.83	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
Conservation	phyloP -0.46	GERP -1.6
Regional constraint	o/e 1.14	unconstrained · MANE · 935 bp · p 0.003 · regional, not allelic
Overall
CADD	18.86	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 0.00647% Admixed American · 3/46,380 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000876%

Overall 0.000406% 6/1,477,518 alleles · very rare exomes 4/1,345,716 · genomes 2/131,802 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00647%	15,460
African / African-American	0.0016%	62,574
South Asian	0.00125%	79,978
European (non-Finnish)	8.93e-05%	1,120,294

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.Ser174Pro
Coding: c.520T>C
MANE Select: NM_000427
Type: single nucleotide variant
Location: chr1:153261469 (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.Ser174Ala 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-ser174pro (accessed [today's date]).

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