Is CNTFR p.Pro4Ala (c.10C>G) pathogenic?

CNTFR p.Pro4Ala (c.10C>G) is classified Uncertain significance in CNTFR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-04). AlphaMissense: likely benign (0.0516); Very rare (popmax 0.000939%, nfe).

How common is CNTFR p.Pro4Ala (c.10C>G) in the general population?

CNTFR p.Pro4Ala (c.10C>G) is very rare (popmax 0.000939%, nfe) (gnomAD).

What do computational predictors say about CNTFR p.Pro4Ala (c.10C>G)?

AlphaMissense predicts likely benign (score 0.0516) — an in-silico prediction, not a clinical call.

CNTFR p.Pro4Ala

c.10C>G · VCV4004461

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0516 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000939%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0516	likely benign
REVEL	0.116	moderately benign-leaning
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.3	GERP -0.26, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	18.27	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000939% European (non-Finnish) · 11/1,170,948 alleles

Filtering AF 0.000504% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000368%

Overall 0.00069% 11/1,594,664 alleles · very rare exomes 7/1,442,540 · genomes 4/152,124 · 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: CNTFR
Protein: p.Pro4Ala
Coding: c.10C>G
MANE Select: NM_147164
Type: single nucleotide variant
Location: chr9:34568972 (GRCh38)
Gene constraint: LOEUF 0.547 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 84.12 · 5 PDB

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

Similar variants

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
CNTFR p.Ala8Val 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-pro4ala (accessed [today's date]).

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