Is LRRTM3 p.Phe417Ser (c.1250T>C) pathogenic?

LRRTM3 p.Phe417Ser (c.1250T>C) is classified Uncertain significance in LRRTM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-08). AlphaMissense: likely pathogenic (0.9449); Very rare (popmax 0.00127%, nfe).

How common is LRRTM3 p.Phe417Ser (c.1250T>C) in the general population?

LRRTM3 p.Phe417Ser (c.1250T>C) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about LRRTM3 p.Phe417Ser (c.1250T>C)?

AlphaMissense predicts likely pathogenic (score 0.9449) — an in-silico prediction, not a clinical call.

LRRTM3 p.Phe417Ser

c.1250T>C · rs1427105596 · VCV2219955

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9449 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9449	likely pathogenic
REVEL	0.697	pathogenic-leaning
SaProt	LLR -4.71	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 170 kb · p 0.26 · regional, not allelic
Overall
CADD	29.8	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 0.00127% European (non-Finnish) · 15/1,180,042 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.000929% 15/1,613,960 alleles · very rare

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: LRRTM3
Protein: p.Phe417Ser
Coding: c.1250T>C
MANE Select: NM_013266 · reported on NM_178011
dbSNP: rs1427105596
Type: single nucleotide variant
Location: chr10:66928166 (GRCh38)

Full LRRTM3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/lrrtm3-p-phe417ser (accessed [today's date]).

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