Is CNTF p.Leu23Pro (c.68T>C) pathogenic?

CNTF p.Leu23Pro (c.68T>C) is classified Uncertain significance in CNTF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely pathogenic (0.8959); Rare (popmax 0.775%, afr).

How common is CNTF p.Leu23Pro (c.68T>C) in the general population?

CNTF p.Leu23Pro (c.68T>C) is rare (popmax 0.775%, afr) (gnomAD).

What do computational predictors say about CNTF p.Leu23Pro (c.68T>C)?

AlphaMissense predicts likely pathogenic (score 0.8959) — an in-silico prediction, not a clinical call.

CNTF p.Leu23Pro

c.68T>C · VCV4231051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8959 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.775%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8959	likely pathogenic · top 4% in CNTF
REVEL	0.705	pathogenic-leaning
SaProt	LLR -11.25	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,766 bp · p 0.055 · regional, not allelic
Overall
CADD	26.7	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 0.775% African / African-American · 582/75,056 alleles

Filtering AF 0.723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.703%

Overall 0.0408% 659/1,614,098 alleles · rare exomes 315/1,461,740 · genomes 344/152,358 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.775%	129
Middle Eastern	0.099%	1,010
Admixed American	0.0533%	1,875
Remaining individualsnot grpmax-eligible	0.0528%	1,894
East Asian	0.00223%	44,878
South Asian	0.0011%	91,082
European (non-Finnish)	0.000339%	294,992

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.Leu23Pro
Coding: c.68T>C
MANE Select: NM_000614
Type: single nucleotide variant
Location: chr11:58622820 (GRCh38)
Gene constraint: LOEUF 1.555 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.84 · 2 PDB
Residue 23: 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-leu23pro (accessed [today's date]).

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