Is TMTC3 p.Lys891Glu (c.2671A>G) pathogenic?

TMTC3 p.Lys891Glu (c.2671A>G) is classified Uncertain significance in TMTC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-11). Ultra-rare (popmax 0.0341%, amr); Associated with Inborn genetic diseases.

What condition is associated with TMTC3 p.Lys891Glu (c.2671A>G)?

TMTC3 p.Lys891Glu (c.2671A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TMTC3 p.Lys891Glu (c.2671A>G) in the general population?

TMTC3 p.Lys891Glu (c.2671A>G) is ultra-rare (popmax 0.0341%, amr) (gnomAD).

TMTC3 p.Lys891Glu

c.2671A>G · rs755684833 · VCV2006192

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0341%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.109	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 47 kb · p 7.2e-07 · regional, not allelic
Overall
CADD	23.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0341% Admixed American · 20/58,704 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.00131% 21/1,608,276 alleles · ultra-rare exomes 21/1,455,970 · genomes 0/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0341%	2,935
East Asian	0.00223%	44,758

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: TMTC3
Protein: p.Lys891Glu
Coding: c.2671A>G
MANE Select: NM_181783
dbSNP: rs755684833
Type: single nucleotide variant
Location: chr12:88195575 (GRCh38)
Gene constraint: LOEUF 0.721 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.83
Residue 891: the 'disordered' region

Full TMTC3 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

TMTC3 p.Ala540Glu Uncertain significance ★★ same condition
TMTC3 p.Arg553Cys Uncertain significance ★★ same condition
TMTC3 p.Asp427Tyr Uncertain significance ★★ same condition
TMTC3 p.Cys778Tyr Uncertain significance ★★ same condition
TMTC3 p.Glu299Gln Uncertain significance ★★ same condition
TMTC3 p.Ile4Val Uncertain significance ★★ same condition
TMTC3 p.Leu239Pro Uncertain significance ★★ same condition
TMTC3 p.Lys758Glu 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/tmtc3-p-lys891glu (accessed [today's date]).

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