Is TMEM127 p.Leu135Pro (c.404T>C) pathogenic?

TMEM127 p.Leu135Pro (c.404T>C) is classified Uncertain significance in TMEM127 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-13). AlphaMissense: likely pathogenic (0.9981); Absent from gnomAD v4.1; Associated with hereditary pheochromocytoma-paraganglioma.

What condition is associated with TMEM127 p.Leu135Pro (c.404T>C)?

TMEM127 p.Leu135Pro (c.404T>C) is associated with hereditary pheochromocytoma-paraganglioma, hereditary neoplastic syndrome (ClinVar).

How common is TMEM127 p.Leu135Pro (c.404T>C) in the general population?

TMEM127 p.Leu135Pro (c.404T>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary pheochromocytoma-paraganglioma inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TMEM127 p.Leu135Pro (c.404T>C)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

TMEM127 p.Leu135Pro

c.404T>C · rs1347547225 · VCV1467916

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary pheochromocytoma-paraganglioma

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic · top 8% in TMEM127
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 12 kb · p 0.42 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

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.Leu135Pro
Coding: c.404T>C
MANE Select: NM_017849
dbSNP: rs1347547225
Type: single nucleotide variant
Location: chr2:96254838 (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 pheochromocytoma-paraganglioma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome

For Hereditary pheochromocytoma-paraganglioma (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

TMEM127 p.Leu135Ile 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
TMEM127 c.409+1G>T Pathogenic/Likely pathogenic ★★ same condition
TMEM127 c.410-1G>C Pathogenic ★★ same condition
TMEM127 c.410-2A>C 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-leu135pro (accessed [today's date]).

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