Is CTR9 p.Met540Val (c.1618A>G) pathogenic?

CTR9 p.Met540Val (c.1618A>G) is classified Uncertain significance in CTR9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-15). AlphaMissense: ambiguous (0.4334); Very rare (popmax 0.00223%, sas); Associated with Inborn genetic diseases.

What condition is associated with CTR9 p.Met540Val (c.1618A>G)?

CTR9 p.Met540Val (c.1618A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CTR9 p.Met540Val (c.1618A>G) in the general population?

CTR9 p.Met540Val (c.1618A>G) is very rare (popmax 0.00223%, sas) (gnomAD).

What do computational predictors say about CTR9 p.Met540Val (c.1618A>G)?

AlphaMissense predicts ambiguous (score 0.4334) — an in-silico prediction, not a clinical call.

CTR9 p.Met540Val

c.1618A>G · VCV4008092

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4334 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4334	ambiguous
REVEL	0.286	benign-leaning
SaProt	LLR -9.75	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 5,532 bp · p 3.5e-22 · regional, not allelic
Overall
CADD	23.5	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 0.00223% South Asian · 2/89,736 alleles

Filtering AF 0.00037% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000139%

Overall 0.000206% 3/1,457,788 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00223%	44,868
European (non-Finnish)	8.48e-05%	1,179,083

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: CTR9
Protein: p.Met540Val
Coding: c.1618A>G
MANE Select: NM_014633
Type: single nucleotide variant
Location: chr11:10766422 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.62 · 21 PDB
Residue 540: an α-helix

Full CTR9 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

Similar variants

CTR9 p.Met540Leu Uncertain significance ★ ⚠ same residue
CTR9 p.Ala644Gly Uncertain significance ★★ ⚠ same condition
CTR9 p.Ala897Gly Uncertain significance ★★ ⚠ same condition
CTR9 p.Arg1074Trp Uncertain significance ★★ ⚠ same condition
CTR9 p.Arg1077Gln Uncertain significance ★★ ⚠ same condition
CTR9 p.Arg1163Gly Uncertain significance ★★ ⚠ same condition
CTR9 p.Arg725Gln Uncertain significance ★★ ⚠ same condition
CTR9 p.Asn175Ser Uncertain significance ★★ ⚠ 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/ctr9-p-met540val (accessed [today's date]).

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