Is CHRNE p.Pro250Ser (c.748C>T) pathogenic?

CHRNE p.Pro250Ser (c.748C>T) is classified Uncertain significance in CHRNE (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-28). AlphaMissense: likely pathogenic (0.9746); Very rare (popmax 0.000678%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHRNE p.Pro250Ser (c.748C>T)?

CHRNE p.Pro250Ser (c.748C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHRNE p.Pro250Ser (c.748C>T) in the general population?

CHRNE p.Pro250Ser (c.748C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about CHRNE p.Pro250Ser (c.748C>T)?

AlphaMissense predicts likely pathogenic (score 0.9746) — an in-silico prediction, not a clinical call.

CHRNE p.Pro250Ser

c.748C>T · rs1245475328 · VCV3144681

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9746 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9746	likely pathogenic
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -13.77	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.9	GERP 0.96, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 4,324 bp · p 7.4e-05 · regional, not allelic
Overall
CADD	27.6	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 0.000678% European (non-Finnish) · 8/1,179,986 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,960 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: CHRNE
Protein: p.Pro250Ser
Coding: c.748C>T
MANE Select: NM_001145536 · reported on NM_000080
dbSNP: rs1245475328
Type: single nucleotide variant
Location: chr17:4901044 (GRCh38)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/chrne-p-pro250ser (accessed [today's date]).

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