Is TMTC3 p.Pro511Thr (c.1531C>A) pathogenic?

TMTC3 p.Pro511Thr (c.1531C>A) is classified Uncertain significance in TMTC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-03). Very rare (popmax 0.00136%, afr); Associated with Inborn genetic diseases.

What condition is associated with TMTC3 p.Pro511Thr (c.1531C>A)?

TMTC3 p.Pro511Thr (c.1531C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TMTC3 p.Pro511Thr (c.1531C>A) in the general population?

TMTC3 p.Pro511Thr (c.1531C>A) is very rare (popmax 0.00136%, afr) (gnomAD).

TMTC3 p.Pro511Thr

c.1531C>A · VCV3971199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00136%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.754	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 47 kb · p 7.2e-07 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% African / African-American · 1/73,422 alleles

Overall 6.35e-05% 1/1,575,810 alleles · very rare exomes 0/1,423,700 · genomes 1/152,110 · 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: TMTC3
Protein: p.Pro511Thr
Coding: c.1531C>A
MANE Select: NM_181783
Type: single nucleotide variant
Location: chr12:88188941 (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-pro511thr (accessed [today's date]).

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