Is TMEM127 p.Cys61Arg (c.181T>C) pathogenic?

TMEM127 p.Cys61Arg (c.181T>C) is classified Uncertain significance in TMEM127 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with TMEM127 p.Cys61Arg (c.181T>C)?

TMEM127 p.Cys61Arg (c.181T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is TMEM127 p.Cys61Arg (c.181T>C) in the general population?

TMEM127 p.Cys61Arg (c.181T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMEM127 p.Cys61Arg (c.181T>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

TMEM127 p.Cys61Arg

c.181T>C · rs1684389727 · VCV2561612

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic · top 3% in TMEM127
REVEL	0.896	moderately pathogenic-leaning
SaProt	LLR -13.83	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 12 kb · p 0.42 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMEM127
Protein: p.Cys61Arg
Coding: c.181T>C
MANE Select: NM_017849
dbSNP: rs1684389727
Type: single nucleotide variant
Location: chr2:96265201 (GRCh38)
Gene constraint: LOEUF 1.587 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.38

Full TMEM127 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMEM127 p.Cys61Ser Uncertain significance ★★ ⚠ same residue
TMEM127 p.Cys61Tyr Uncertain significance ★★ ⚠ same residue
TMEM127 p.Cys61fs Pathogenic ★★ same residue
TMEM127 c.245-1G>A Pathogenic/Likely pathogenic ★★ same condition
TMEM127 c.245-1G>C Pathogenic/Likely pathogenic ★★ same condition
TMEM127 c.409+1G>T Pathogenic/Likely pathogenic ★★ same condition
TMEM127 c.410-2A>G Pathogenic/Likely pathogenic ★★ same condition
TMEM127 p.Gln139Ter Pathogenic/Likely pathogenic ★★ 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/tmem127-p-cys61arg (accessed [today's date]).

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