Is TMIE p.Pro43fs (c.122_125dup) pathogenic?

TMIE p.Pro43fs (c.122125dup) is classified Pathogenic/Likely pathogenic in TMIE (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-01). Very rare (popmax 0.00988%, sas); Associated with autosomal recessive nonsyndromic hearing loss 6.

How common is TMIE p.Pro43fs (c.122_125dup) in the general population?

TMIE p.Pro43fs (c.122_125dup) is very rare (popmax 0.00988%, sas) (gnomAD).

TMIE p.Pro43fs

Q: What condition is associated with TMIE p.Pro43fs (c.122_125dup)?

TMIE p.Pro43fs (c.122_125dup) is associated with autosomal recessive nonsyndromic hearing loss 6, sensorineural hearing loss disorder (ClinVar).

c.122_125dup · rs876661301 · VCV984396

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Conditions

autosomal recessive nonsyndromic hearing loss 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.4	GERP 0.62, phastCons 1
Region caveats
Repeat context	tandem	(CCCAAG)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00988% South Asian · 9/91,086 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.000558% 9/1,614,060 alleles · very rare exomes 9/1,461,736 · genomes 0/152,324 · 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: TMIE
Protein: p.Pro43fs
Coding: c.122_125dup
MANE Select: NM_147196
dbSNP: rs876661301
Type: Duplication
Location: chr3:46705816 (GRCh38)
Gene constraint: LOEUF 1.475 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.41

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

Disease context

autosomal recessive nonsyndromic hearing loss 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: sensorineural hearing loss disorder

Similar variants

TMIE p.Pro43Leu Uncertain significance ★★ ⚠ same residue
TMIE p.Arg84Trp Likely pathogenic ★★ same condition
TMIE p.Glu31Gly Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMIE c.-154G>A Uncertain significance ★★ same condition
TMIE c.*253G>A Uncertain significance ★★ same condition
TMIE p.Leu22Phe Uncertain significance ★★ ⚠ same condition
TMIE c.-37C>A Benign/Likely benign ★★ same condition
TMIE c.*51C>T Benign/Likely benign ★★ 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/tmie-p-pro43fs (accessed [today's date]).

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