Is LETM1 p.Pro100Ser (c.298C>T) pathogenic?

LETM1 p.Pro100Ser (c.298C>T) is classified Uncertain significance in LETM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0828); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with LETM1 p.Pro100Ser (c.298C>T)?

LETM1 p.Pro100Ser (c.298C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LETM1 p.Pro100Ser (c.298C>T) in the general population?

LETM1 p.Pro100Ser (c.298C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about LETM1 p.Pro100Ser (c.298C>T)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

LETM1 p.Pro100Ser

c.298C>T · VCV4097344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -6.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 14 kb · p 0.059 · regional, not allelic
Overall
CADD	14.29	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: LETM1
Protein: p.Pro100Ser
Coding: c.298C>T
MANE Select: NM_012318
Type: single nucleotide variant
Location: chr4:1841643 (GRCh38)
Gene constraint: LOEUF 0.881 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.36 · 2 PDB

Full LETM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LETM1 p.Ala178Val Uncertain significance ★★ ⚠ same condition
LETM1 p.Arg106His Uncertain significance ★★ ⚠ same condition
LETM1 p.Arg112Cys Uncertain significance ★★ ⚠ same condition
LETM1 p.Arg156Gln Uncertain significance ★★ ⚠ same condition
LETM1 p.Arg307Cys Uncertain significance ★★ ⚠ same condition
LETM1 p.Arg307His Uncertain significance ★★ ⚠ same condition
LETM1 p.Arg323Gln Uncertain significance ★★ ⚠ same condition
LETM1 p.Arg351Gln Uncertain significance ★★ ⚠ same condition

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/letm1-p-pro100ser (accessed [today's date]).

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