Is TMEM127 p.Pro87= (c.261C>G) pathogenic?

TMEM127 p.Pro87= (c.261C>G) is classified Likely benign in TMEM127 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-05). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TMEM127 p.Pro87= (c.261C>G)?

TMEM127 p.Pro87= (c.261C>G) is associated with hereditary neoplastic syndrome, hereditary pheochromocytoma-paraganglioma (ClinVar).

How common is TMEM127 p.Pro87= (c.261C>G) in the general population?

TMEM127 p.Pro87= (c.261C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

TMEM127 p.Pro87=

c.261C>G · rs1447112240 · VCV1554724

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.52	GERP -3.5, phastCons 0.99
Overall
CADD	8.882	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.2e-05% 1/1,614,196 alleles · very rare exomes 1/1,461,868 · genomes 0/152,328 · 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: TMEM127
Protein: p.Pro87=
Coding: c.261C>G
MANE Select: NM_017849
dbSNP: rs1447112240
Type: single nucleotide variant
Location: chr2:96254981 (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

Also linked: hereditary pheochromocytoma-paraganglioma

Similar variants

TMEM127 p.Pro87Ala Uncertain significance ★★ ⚠ same residue
TMEM127 p.Pro87Arg Uncertain significance ★ ⚠ same residue
TMEM127 p.Pro87Ser Uncertain significance ★ ⚠ same residue
TMEM127 p.Pro87Leu Uncertain significance ★ ⚠ same residue
TMEM127 c.245-1G>A Pathogenic/Likely pathogenic ★★ same condition
TMEM127 c.245-1G>C Pathogenic/Likely pathogenic ★★ same condition
TMEM127 c.245-1G>T Pathogenic/Likely pathogenic ★★ same condition
TMEM127 c.245-2A>G 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-pro87 (accessed [today's date]).

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