Is CNTFR p.Leu76Phe (c.226C>T) pathogenic?

CNTFR p.Leu76Phe (c.226C>T) is classified Uncertain significance in CNTFR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.2737); Very rare (popmax 6.84e-05%).

How common is CNTFR p.Leu76Phe (c.226C>T) in the general population?

CNTFR p.Leu76Phe (c.226C>T) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about CNTFR p.Leu76Phe (c.226C>T)?

AlphaMissense predicts likely benign (score 0.2737) — an in-silico prediction, not a clinical call.

CNTFR p.Leu76Phe

c.226C>T · VCV4655059

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2737	likely benign
REVEL	0.358	indeterminate
SaProt	LLR -11.98	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.77, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	23.2	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 6.84e-05%

Overall 6.84e-05% 1/1,461,768 alleles · very rare

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.Leu76Phe
Coding: c.226C>T
MANE Select: NM_147164
Type: single nucleotide variant
Location: chr9:34564692 (GRCh38)
Gene constraint: LOEUF 0.547 · pLI 0.91 (gnomAD)
Structure: AlphaFold pLDDT 84.12 · 5 PDB
Residue 76: a disulfide bond; 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 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-leu76phe (accessed [today's date]).

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