Is CNTF p.Ser20Pro (c.58T>C) pathogenic?

CNTF p.Ser20Pro (c.58T>C) is classified Uncertain significance in CNTF (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: likely pathogenic (0.7414); Ultra-rare (popmax 0.0147%, afr).

How common is CNTF p.Ser20Pro (c.58T>C) in the general population?

CNTF p.Ser20Pro (c.58T>C) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about CNTF p.Ser20Pro (c.58T>C)?

AlphaMissense predicts likely pathogenic (score 0.7414) — an in-silico prediction, not a clinical call.

CNTF p.Ser20Pro

c.58T>C · rs538707475 · VCV2210372

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7414 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7414	likely pathogenic
REVEL	0.21	benign-leaning
SaProt	LLR -13.52	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.56, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 1,766 bp · p 0.055 · regional, not allelic
Overall
CADD	22.5	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 0.0147% African / African-American · 11/75,054 alleles

Filtering AF 0.00814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00632%

Overall 0.000743% 12/1,614,072 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,823
South Asian	0.0011%	91,076

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.Ser20Pro
Coding: c.58T>C
MANE Select: NM_000614
dbSNP: rs538707475
Type: single nucleotide variant
Location: chr11:58622810 (GRCh38)
Gene constraint: LOEUF 1.555 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.84 · 2 PDB
Residue 20: 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-ser20pro (accessed [today's date]).

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