Is CNTFR p.Arg37Cys (c.109C>T) pathogenic?

CNTFR p.Arg37Cys (c.109C>T) is classified Uncertain significance in CNTFR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-22). AlphaMissense: ambiguous (0.4569); Very rare (popmax 0.00223%, eas).

How common is CNTFR p.Arg37Cys (c.109C>T) in the general population?

CNTFR p.Arg37Cys (c.109C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CNTFR p.Arg37Cys (c.109C>T)?

AlphaMissense predicts ambiguous (score 0.4569) — an in-silico prediction, not a clinical call.

CNTFR p.Arg37Cys

c.109C>T · VCV3834632

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4569 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4569	ambiguous
REVEL	0.155	moderately benign-leaning
SaProt	LLR -12.00	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 11 kb · p 0.23 · 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 0.00223% East Asian · 1/44,872 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000821% 12/1,461,652 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
Admixed American	0.00167%	60,022
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	0.000763%	131,112

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: CNTFR
Protein: p.Arg37Cys
Coding: c.109C>T
MANE Select: NM_147164
Type: single nucleotide variant
Location: chr9:34564809 (GRCh38)
Gene constraint: LOEUF 0.547 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 84.12 · 5 PDB
Residue 37: a β-strand; the ig-like c2-type domain

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

Similar variants

CNTFR p.Arg37His Uncertain significance ★ ⚠ same residue
CNTFR c.438-1G>A Uncertain significance ★ same type
CNTFR p.Ala297Thr Uncertain significance ★ ⚠ same type
CNTFR p.Ala313Ser Uncertain significance ★ ⚠ same type
CNTFR p.Ala316Val Uncertain significance ★ ⚠ same type
CNTFR p.Ala367Thr Uncertain significance ★ ⚠ same type
CNTFR p.Ala3Val Uncertain significance ★ ⚠ same type
CNTFR p.Ala54Val 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/cntfr-p-arg37cys (accessed [today's date]).

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