Is LRRTM3 p.Ser322Phe (c.965C>T) pathogenic?

LRRTM3 p.Ser322Phe (c.965C>T) is classified Uncertain significance in LRRTM3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-31). AlphaMissense: ambiguous (0.5461); Very rare (popmax 0.000169%, nfe).

How common is LRRTM3 p.Ser322Phe (c.965C>T) in the general population?

LRRTM3 p.Ser322Phe (c.965C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about LRRTM3 p.Ser322Phe (c.965C>T)?

AlphaMissense predicts ambiguous (score 0.5461) — an in-silico prediction, not a clinical call.

LRRTM3 p.Ser322Phe

c.965C>T · VCV3868825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5461	ambiguous
REVEL	0.204	benign-leaning
SaProt	LLR -8.47	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 170 kb · p 0.26 · regional, not allelic
Overall
CADD	29.5	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 0.000169% European (non-Finnish) · 2/1,180,038 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,194 alleles · very rare exomes 2/1,461,886 · genomes 0/152,308 · joint denominator

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.Ser322Phe
Coding: c.965C>T
MANE Select: NM_178011
Type: single nucleotide variant
Location: chr10:66927881 (GRCh38)
Gene constraint: LOEUF 0.721 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.23
Residue 322: the lrrct domain

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

Similar variants

LRRTM3 p.Ala223Val Uncertain significance ★ ⚠ same type
LRRTM3 p.Ala372Ser Uncertain significance ★ ⚠ same type
LRRTM3 p.Ala401Ser Uncertain significance ★ ⚠ same type
LRRTM3 p.Ala581Thr Uncertain significance ★ ⚠ same type
LRRTM3 p.Arg109Cys Uncertain significance ★ ⚠ same type
LRRTM3 p.Arg109His Uncertain significance ★ ⚠ same type
LRRTM3 p.Arg282Leu Uncertain significance ★ ⚠ same type
LRRTM3 p.Arg444Leu Uncertain significance ★ ⚠ 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/lrrtm3-p-ser322phe (accessed [today's date]).

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