Is CNTF p.Leu165Arg (c.494T>G) pathogenic?

CNTF p.Leu165Arg (c.494T>G) is classified Uncertain significance in CNTF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-16). AlphaMissense: likely pathogenic (0.937); Very rare (popmax 0.000339%, nfe).

How common is CNTF p.Leu165Arg (c.494T>G) in the general population?

CNTF p.Leu165Arg (c.494T>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CNTF p.Leu165Arg (c.494T>G)?

AlphaMissense predicts likely pathogenic (score 0.937) — an in-silico prediction, not a clinical call.

CNTF p.Leu165Arg

c.494T>G · rs1441290691 · VCV2485986

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.937	likely pathogenic · top 2% in CNTF
REVEL	0.585	indeterminate
SaProt	LLR -13.02	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,766 bp · p 0.055 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,944 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,950 alleles · very rare exomes 4/1,461,758 · genomes 0/152,192 · 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: CNTF
Protein: p.Leu165Arg
Coding: c.494T>G
MANE Select: NM_000614
dbSNP: rs1441290691
Type: single nucleotide variant
Location: chr11:58624413 (GRCh38)
Gene constraint: LOEUF 1.555 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.84 · 2 PDB
Residue 165: an α-helix

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

Similar variants

CNTF p.Asn49Ser Benign ★★ same type
CNTF p.Ala108Thr Uncertain significance ★ ⚠ same type
CNTF p.Ala117Val Uncertain significance ★ ⚠ same type
CNTF p.Arg136His Uncertain significance ★ ⚠ same type
CNTF p.Arg13His Uncertain significance ★ ⚠ same type
CNTF p.Arg177His Uncertain significance ★ ⚠ same type
CNTF p.Arg19His Uncertain significance ★ ⚠ same type
CNTF p.Arg19Leu 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/cntf-p-leu165arg (accessed [today's date]).

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