Is CTR9 p.Arg667His (c.2000G>A) pathogenic?

CTR9 p.Arg667His (c.2000G>A) is classified Uncertain significance in CTR9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-09). AlphaMissense: likely pathogenic (0.9903); Very rare (popmax 0.0011%, sas).

How common is CTR9 p.Arg667His (c.2000G>A) in the general population?

CTR9 p.Arg667His (c.2000G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CTR9 p.Arg667His (c.2000G>A)?

AlphaMissense predicts likely pathogenic (score 0.9903) — an in-silico prediction, not a clinical call.

CTR9 p.Arg667His

c.2000G>A · rs753928657 · VCV1037903

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9903 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9903	likely pathogenic
REVEL	0.6	indeterminate
SaProt	LLR -6.52	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 5,532 bp · p 3.5e-22 · regional, not allelic
Overall
CADD	32.0	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 0.0011% South Asian · 1/91,072 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00031% 5/1,613,956 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
South Asiangrpmax	0.0011%	91,072
European (non-Finnish)	0.000254%	393,334

Ashkenazi Jewish 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.Arg667His
Coding: c.2000G>A
MANE Select: NM_014633
dbSNP: rs753928657
Type: single nucleotide variant
Location: chr11:10768382 (GRCh38)
Gene constraint: LOEUF 0.368 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 76.62 · 21 PDB
Residue 667: an α-helix

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

Similar variants

CTR9 p.Asn455Ser Likely pathogenic ★★ same type
CTR9 p.Ile17Thr Pathogenic/Likely pathogenic ★★ same type
CTR9 p.Pro25Arg Pathogenic/Likely pathogenic ★★ same type
CTR9 c.1960+3G>A Uncertain significance ★★ same type
CTR9 c.2109+4A>G Uncertain significance ★★ same type
CTR9 c.2445-3T>C Uncertain significance ★★ same type
CTR9 c.45+5G>T Uncertain significance ★★ same type
CTR9 c.593-8T>A Uncertain significance ★★ same type

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-arg667his (accessed [today's date]).

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