Is TMCO1 p.Arg87Pro (c.260G>C) pathogenic?

TMCO1 p.Arg87Pro (c.260G>C) is classified Uncertain significance in TMCO1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-07). AlphaMissense: likely pathogenic (0.9974); Very rare (popmax 6.2e-05%).

How common is TMCO1 p.Arg87Pro (c.260G>C) in the general population?

TMCO1 p.Arg87Pro (c.260G>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about TMCO1 p.Arg87Pro (c.260G>C)?

AlphaMissense predicts likely pathogenic (score 0.9974) — an in-silico prediction, not a clinical call.

TMCO1 p.Arg87Pro

c.260G>C · rs763875549 · VCV1979746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9974	likely pathogenic · top 9% in TMCO1
REVEL	0.498	indeterminate
SaProt	LLR -8.99	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.92, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 41 kb · p 0.00047 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R138P vs ClinVar R87P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,611,890 alleles · very rare exomes 0/1,460,680 · genomes 1/151,210 · 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: TMCO1
Protein: p.Arg87Pro
Coding: c.260G>C
MANE Select: NM_019026
dbSNP: rs763875549
Type: single nucleotide variant
Location: chr1:165752165 (GRCh38)
Gene constraint: LOEUF 1.404 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.41 · 1 PDB
Residue 138 UniProt numbering: a UniProt-annotated variant site (in cfsmr1)

Full TMCO1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMCO1 p.Arg87Ter Pathogenic ★ same residue
TMCO1 p.Arg155Ter Pathogenic/Likely pathogenic ★★ same type
TMCO1 p.Arg63Ter Pathogenic ★★ same type
TMCO1 p.Gln126Ter Pathogenic/Likely pathogenic ★★ same type
TMCO1 p.Asn106Ser Uncertain significance ★★ ⚠ same type
TMCO1 p.Ser153Leu Uncertain significance ★★ ⚠ same type
TMCO1 p.Thr18Pro Uncertain significance ★★ ⚠ same type
TMCO1 c.148+136T>C Likely benign ★★ same type

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/tmco1-p-arg87pro (accessed [today's date]).

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