Is CTR9 p.Glu376Lys (c.1126G>A) pathogenic?

CTR9 p.Glu376Lys (c.1126G>A) is classified Conflicting classifications of pathogenicity in CTR9 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-07-29). AlphaMissense: likely pathogenic (0.9984); Very rare (popmax 6.2e-05%); Associated with CTR9-related neurodevelopmental disorder.

What condition is associated with CTR9 p.Glu376Lys (c.1126G>A)?

CTR9 p.Glu376Lys (c.1126G>A) is associated with CTR9-related neurodevelopmental disorder (ClinVar).

How common is CTR9 p.Glu376Lys (c.1126G>A) in the general population?

CTR9 p.Glu376Lys (c.1126G>A) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about CTR9 p.Glu376Lys (c.1126G>A)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

CTR9 p.Glu376Lys

c.1126G>A · rs869312709 · VCV224155

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CTR9-related neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic · top 8% in CTR9
REVEL	0.537	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 1,051 bp · p 1.2e-12 · regional, not allelic
Overall
CADD	33.0	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 6.2e-05%

Overall 6.2e-05% 1/1,613,794 alleles · very rare exomes 1/1,461,594 · genomes 0/152,200 · 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: CTR9
Protein: p.Glu376Lys
Coding: c.1126G>A
MANE Select: NM_014633
dbSNP: rs869312709
Type: single nucleotide variant
Location: chr11:10763811 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.62 · 21 PDB
Residue 376: an α-helix

Full CTR9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CTR9-related neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTR9 p.Asn455Ser Likely pathogenic ★★ same condition
CTR9 p.Ile17Thr Pathogenic/Likely pathogenic ★★ same condition
CTR9 p.Pro25Arg Pathogenic/Likely pathogenic ★★ same condition
CTR9 c.46-1G>T Pathogenic ★ same condition
CTR9 p.Arg878Gln Likely pathogenic ★ ⚠ same condition
CTR9 p.Cys85Tyr Likely pathogenic ★ same condition
CTR9 p.Glu15Lys Likely pathogenic ★ same condition
CTR9 p.Glu26Gln Likely 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/ctr9-p-glu376lys (accessed [today's date]).

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