Is TMTC3 p.Pro613Arg (c.1838C>G) pathogenic?

TMTC3 p.Pro613Arg (c.1838C>G) is classified Uncertain significance in TMTC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-11). Ultra-rare (popmax 0.0217%, amr); Associated with Inborn genetic diseases.

What condition is associated with TMTC3 p.Pro613Arg (c.1838C>G)?

TMTC3 p.Pro613Arg (c.1838C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TMTC3 p.Pro613Arg (c.1838C>G) in the general population?

TMTC3 p.Pro613Arg (c.1838C>G) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

TMTC3 p.Pro613Arg

c.1838C>G · VCV4187665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.166	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 47 kb · p 7.2e-07 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/59,960 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00217% 35/1,613,278 alleles · ultra-rare exomes 34/1,461,198 · genomes 1/152,080 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,612
Remaining individualsnot grpmax-eligible	0.0048%	20,814
East Asian	0.00223%	44,746
European (non-Finnish)	0.00153%	65,537

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.Pro613Arg
Coding: c.1838C>G
MANE Select: NM_181783
Type: single nucleotide variant
Location: chr12:88192735 (GRCh38)
Gene constraint: LOEUF 0.721 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.83

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-pro613arg (accessed [today's date]).

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