Is GLMN p.Pro254Arg (c.761C>G) pathogenic?

GLMN p.Pro254Arg (c.761C>G) is classified Conflicting classifications of pathogenicity in GLMN (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2018-01-12). AlphaMissense: likely benign (0.1344); Rare (popmax 0.963%, eas); Associated with glomuvenous malformation.

What condition is associated with GLMN p.Pro254Arg (c.761C>G)?

GLMN p.Pro254Arg (c.761C>G) is associated with glomuvenous malformation, blue rubber bleb nevus (ClinVar).

How common is GLMN p.Pro254Arg (c.761C>G) in the general population?

GLMN p.Pro254Arg (c.761C>G) is rare (popmax 0.963%, eas) (gnomAD).

What do computational predictors say about GLMN p.Pro254Arg (c.761C>G)?

AlphaMissense predicts likely benign (score 0.1344) — an in-silico prediction, not a clinical call.

GLMN p.Pro254Arg

c.761C>G · rs145762716 · VCV298140

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1344 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.963%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

glomuvenous malformation

Computational evidence

Protein change
AlphaMissense	0.1344	likely benign
REVEL	0.231	benign-leaning
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 51 kb · p 0.0058 · regional, not allelic
Overall
CADD	23.0	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

Grpmax group 0.963% East Asian · 432/44,840 alleles

Filtering AF 0.888% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.859%

Overall 0.0288% 465/1,612,426 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.963%	104
Remaining individualsnot grpmax-eligible	0.0288%	3,469
South Asian	0.0154%	6,502
European (non-Finnish)	8.48e-05%	1,178,684

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: GLMN
Protein: p.Pro254Arg
Coding: c.761C>G
MANE Select: NM_053274
dbSNP: rs145762716
Type: single nucleotide variant
Location: chr1:92271627 (GRCh38)
Gene constraint: LOEUF 1.705 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 88.41 · 1 PDB
Residue 254: the 'alpha-helical region with structural similarity to heat repeats' region

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

Disease context

glomuvenous malformation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: blue rubber bleb nevus

Similar variants

GLMN p.Cys36Ter Pathogenic/Likely pathogenic ★★ same condition
GLMN p.Ala140Pro Uncertain significance ★★ ⚠ same condition
GLMN p.Ala146Val Uncertain significance ★★ ⚠ same condition
GLMN p.Ser411Thr Uncertain significance ★★ ⚠ same condition
GLMN p.Val191Phe Uncertain significance ★★ ⚠ same condition
GLMN c.165+10A>G Benign/Likely benign ★★ same condition
GLMN c.977+7T>A Benign ★★ same condition
GLMN c.977+9G>A Benign ★★ 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/glmn-p-pro254arg (accessed [today's date]).

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