Is LETM1 p.Arg307= (c.921T>C) pathogenic?

LETM1 p.Arg307= (c.921T>C) is classified Likely benign in LETM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-12). Very rare (popmax 0.0033%, sas).

How common is LETM1 p.Arg307= (c.921T>C) in the general population?

LETM1 p.Arg307= (c.921T>C) is very rare (popmax 0.0033%, sas) (gnomAD).

LETM1 p.Arg307=

c.921T>C · VCV4966057

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.3	GERP -3.8
Overall
CADD	3.94	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0033% South Asian · 3/91,006 alleles

Filtering AF 0.000876% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000744% 12/1,612,876 alleles · very rare exomes 11/1,460,770 · genomes 1/152,106 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0144%	6,932
South Asiangrpmax	0.0033%	30,335

Remaining individuals 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: LETM1
Protein: p.Arg307=
Coding: c.921T>C
MANE Select: NM_012318
Type: single nucleotide variant
Location: chr4:1832903 (GRCh38)
Gene constraint: LOEUF 0.881 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.36 · 2 PDB
Residue 307: the letm1 rbd domain

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

Similar variants

LETM1 p.Arg307Cys Uncertain significance ★★ ⚠ same residue
LETM1 p.Arg307His Uncertain significance ★★ ⚠ same residue
LETM1 p.Ala178Val Uncertain significance ★★ ⚠ same type
LETM1 p.Arg106His Uncertain significance ★★ ⚠ same type
LETM1 p.Arg112Cys Uncertain significance ★★ ⚠ same type
LETM1 p.Arg156Gln Uncertain significance ★★ ⚠ same type
LETM1 p.Arg323Gln Uncertain significance ★★ ⚠ same type
LETM1 p.Arg351Gln 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/letm1-p-arg307 (accessed [today's date]).

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