Is LRTOMT p.Ser74= (c.222A>G) pathogenic?

LRTOMT p.Ser74= (c.222A>G) is classified Conflicting classifications of pathogenicity in LRTOMT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-20). Rare (popmax 0.354%, eas); Associated with autosomal recessive nonsyndromic hearing loss 63.

What condition is associated with LRTOMT p.Ser74= (c.222A>G)?

LRTOMT p.Ser74= (c.222A>G) is associated with autosomal recessive nonsyndromic hearing loss 63 (ClinVar).

How common is LRTOMT p.Ser74= (c.222A>G) in the general population?

LRTOMT p.Ser74= (c.222A>G) is rare (popmax 0.354%, eas) (gnomAD).

LRTOMT p.Ser74=

c.222A>G · rs397516626 · VCV44038

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.354%, eas)

Conditions

autosomal recessive nonsyndromic hearing loss 63

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 0.18	GERP -0.43, phastCons 0.17
Overall
CADD	9.758	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.354% East Asian · 145/40,916 alleles

Filtering AF 0.307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.29%

Overall 0.0101% 156/1,550,342 alleles · rare exomes 144/1,398,164 · genomes 12/152,178 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.354%	282
Remaining individualsnot grpmax-eligible	0.00333%	30,055
European (non-Finnish)	0.000785%	127,438

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: LRTOMT
Protein: p.Ser74=
Coding: c.222A>G
dbSNP: rs397516626
Type: single nucleotide variant
Location: chr11:72106074 (GRCh38)
Gene constraint: LOEUF 1.315 · pLI <0.01 (gnomAD)

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

Disease context

autosomal recessive nonsyndromic hearing loss 63 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LRTOMT c.358+4A>C Pathogenic/Likely pathogenic ★★ same condition
LRTOMT p.Arg81Gln Pathogenic/Likely pathogenic ★★ same condition
ANAPC15 p.Pro99Leu Uncertain significance ★★ ⚠ same condition
LRTOMT c.-123T>C Uncertain significance ★★ same condition
LRTOMT c.-254G>T Uncertain significance ★★ same condition
LRTOMT c.*1488T>G Uncertain significance ★★ same condition
LRTOMT p.Arg54Gln Uncertain significance ★★ same condition
LRTOMT p.Gly180Ser 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/lrtomt-p-ser74 (accessed [today's date]).

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