Is CTR9 p.Thr498Ser (c.1493C>G) pathogenic?

CTR9 p.Thr498Ser (c.1493C>G) is classified Uncertain significance in CTR9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-22). AlphaMissense: likely pathogenic (0.5824); Very rare (popmax 0.00636%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTR9 p.Thr498Ser (c.1493C>G)?

CTR9 p.Thr498Ser (c.1493C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CTR9 p.Thr498Ser (c.1493C>G) in the general population?

CTR9 p.Thr498Ser (c.1493C>G) is very rare (popmax 0.00636%, nfe) (gnomAD).

What do computational predictors say about CTR9 p.Thr498Ser (c.1493C>G)?

AlphaMissense predicts likely pathogenic (score 0.5824) — an in-silico prediction, not a clinical call.

CTR9 p.Thr498Ser

c.1493C>G · rs374946934 · VCV1001643

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00636%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5824	likely pathogenic
REVEL	0.277	benign-leaning
SaProt	LLR -8.14	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	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	22.0	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 0.00636% European (non-Finnish) · 75/1,179,660 alleles

Filtering AF 0.00519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00474%

Overall 0.00521% 84/1,613,452 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.008%	12,494
European (non-Finnish)grpmax	0.00636%	15,729
Admixed American	0.00333%	29,985
African / African-American	0.00134%	74,894
South Asian	0.0011%	91,020

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr498Ser
Coding: c.1493C>G
MANE Select: NM_014633
dbSNP: rs374946934
Type: single nucleotide variant
Location: chr11:10764627 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.62 · 21 PDB
Residue 498: 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.Thr498= Benign ★★ 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-thr498ser (accessed [today's date]).

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