Is GLMN p.Ala140Pro (c.418G>C) pathogenic?

GLMN p.Ala140Pro (c.418G>C) is classified Uncertain significance in GLMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-27). AlphaMissense: likely benign (0.1597); Ultra-rare (popmax 0.0169%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GLMN p.Ala140Pro (c.418G>C)?

GLMN p.Ala140Pro (c.418G>C) is associated with Inborn genetic diseases, glomuvenous malformation (ClinVar).

How common is GLMN p.Ala140Pro (c.418G>C) in the general population?

GLMN p.Ala140Pro (c.418G>C) is ultra-rare (popmax 0.0169%, nfe) (gnomAD).

What do computational predictors say about GLMN p.Ala140Pro (c.418G>C)?

AlphaMissense predicts likely benign (score 0.1597) — an in-silico prediction, not a clinical call.

GLMN p.Ala140Pro

c.418G>C · rs754543701 · VCV2401168

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1597 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1597	likely benign
REVEL	0.299	indeterminate
SaProt	LLR -5.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -2.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 51 kb · p 0.0058 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.0169% European (non-Finnish) · 198/1,168,162 alleles

Filtering AF 0.015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.013% 208/1,600,812 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0169%	5,900
Remaining individualsnot grpmax-eligible	0.0129%	7,748
African / African-American	0.00134%	74,636
South Asian	0.0011%	90,842

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.Ala140Pro
Coding: c.418G>C
MANE Select: NM_053274
dbSNP: rs754543701
Type: single nucleotide variant
Location: chr1:92289128 (GRCh38)
Gene constraint: LOEUF 1.705 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 88.41 · 1 PDB
Residue 140: the 'alpha-helical region with structural similarity to heat repeats' region; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: glomuvenous malformation

Similar variants

GLMN c.1214+2T>C Pathogenic/Likely pathogenic ★★ same condition
GLMN p.Cys36Ter Pathogenic/Likely pathogenic ★★ same condition
GLMN p.Ala146Val Uncertain significance ★★ ⚠ same condition
GLMN p.Gln117Glu Uncertain significance ★★ ⚠ same condition
GLMN p.Met168Val 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

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-ala140pro (accessed [today's date]).

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