Is LORICRIN p.Ser169Phe (c.506C>T) pathogenic?

LORICRIN p.Ser169Phe (c.506C>T) is classified Benign/Likely benign in LORICRIN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-26). AlphaMissense: likely benign (0.1903); Ultra-rare (popmax 0.0259%, nfe).

How common is LORICRIN p.Ser169Phe (c.506C>T) in the general population?

LORICRIN p.Ser169Phe (c.506C>T) is ultra-rare (popmax 0.0259%, nfe) (gnomAD).

What do computational predictors say about LORICRIN p.Ser169Phe (c.506C>T)?

AlphaMissense predicts likely benign (score 0.1903) — an in-silico prediction, not a clinical call.

LORICRIN p.Ser169Phe

c.506C>T · rs772586615 · VCV2074000

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1903 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0259%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1903	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -10.23	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.28	GERP -1.8
Regional constraint	o/e 1.14	unconstrained · MANE · 935 bp · p 0.003 · regional, not allelic
Overall
CADD	16.74	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 0.0259% European (non-Finnish) · 292/1,128,698 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0225%

Overall 0.0395% 589/1,491,208 alleles · ultra-rare exomes 513/1,353,128 · genomes 76/138,080 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.571%	175
Remaining individualsnot grpmax-eligible	0.0911%	1,098
European (non-Finnish)grpmax	0.0259%	3,865
Admixed American	0.00423%	23,615

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser169Phe
Coding: c.506C>T
MANE Select: NM_000427
dbSNP: rs772586615
Type: single nucleotide variant
Location: chr1:153261455 (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.Ser285Phe 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-ser169phe (accessed [today's date]).

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