Is LETM1 p.Ser3Phe (c.8C>T) pathogenic?

LETM1 p.Ser3Phe (c.8C>T) is classified Uncertain significance in LETM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-27). AlphaMissense: likely pathogenic (0.566); Ultra-rare (popmax 0.0253%, afr); Associated with Inborn genetic diseases.

What condition is associated with LETM1 p.Ser3Phe (c.8C>T)?

LETM1 p.Ser3Phe (c.8C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LETM1 p.Ser3Phe (c.8C>T) in the general population?

LETM1 p.Ser3Phe (c.8C>T) is ultra-rare (popmax 0.0253%, afr) (gnomAD).

What do computational predictors say about LETM1 p.Ser3Phe (c.8C>T)?

AlphaMissense predicts likely pathogenic (score 0.566) — an in-silico prediction, not a clinical call.

LETM1 p.Ser3Phe

c.8C>T · rs1015073272 · VCV1407967

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.566 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.566	likely pathogenic
REVEL	0.129	moderately benign-leaning
SaProt	LLR -9.01	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 0.93, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 14 kb · p 0.059 · regional, not allelic
Overall
CADD	24.2	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 0.0253% African / African-American · 16/63,364 alleles

Filtering AF 0.0158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00163% 20/1,224,272 alleles · ultra-rare exomes 6/1,072,704 · genomes 14/151,568 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0253%	3,960
Remaining individualsnot grpmax-eligible	0.00451%	22,159
Admixed American	0.00434%	23,032
South Asian	0.00367%	27,276

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.Ser3Phe
Coding: c.8C>T
MANE Select: NM_012318
dbSNP: rs1015073272
Type: single nucleotide variant
Location: chr4:1855943 (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-ser3phe (accessed [today's date]).

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