Is CHRNA7 p.Val274Ile (c.820G>A) pathogenic?

CHRNA7 p.Val274Ile (c.820G>A) is classified Uncertain significance in CHRNA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely pathogenic (0.6313); Very rare (popmax 0.00616%, eas).

How common is CHRNA7 p.Val274Ile (c.820G>A) in the general population?

CHRNA7 p.Val274Ile (c.820G>A) is very rare (popmax 0.00616%, eas) (gnomAD).

What do computational predictors say about CHRNA7 p.Val274Ile (c.820G>A)?

AlphaMissense predicts likely pathogenic (score 0.6313) — an in-silico prediction, not a clinical call.

CHRNA7 p.Val274Ile

c.820G>A · VCV4228474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6313 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00616%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6313	likely pathogenic
REVEL	0.661	pathogenic-leaning
SaProt	LLR -8.61	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.04	constrained · MANE · 51 kb · p 3.4e-38 · regional, not allelic
Overall
CADD	27.3	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 0.00616% East Asian · 2/32,456 alleles

Filtering AF 0.00333% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00281%

Overall 0.00418% 27/645,452 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00616%	16,228
European (non-Finnish)	0.00511%	19,583
African / African-American	0.00468%	21,380
Remaining individualsnot grpmax-eligible	0.00344%	29,094
Admixed American	0.00246%	40,670
South Asian	0.00209%	47,932

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: CHRNA7
Protein: p.Val274Ile
Coding: c.820G>A
MANE Select: NM_000746
Type: single nucleotide variant
Location: chr15:32159595 (GRCh38)
Gene constraint: LOEUF 1.064 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 51 PDB
Residue 274: an α-helix

Full CHRNA7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRNA7 p.Asn381Asp Uncertain significance ★★ ⚠ same type
CHRNA7 p.Val374Met Uncertain significance ★★ ⚠ same type
CHRNA7 c.196-4G>T Likely benign ★★ same type
CHRNA7 c.240+113C>A Benign ★★ same type
CHRNA7 c.350+304G>A Likely benign ★★ same type
CHRNA7 c.55+77G>A Benign ★★ same type
CHRNA7 c.598+86C>T Benign ★★ same type
CHRNA7 c.599-111T>A Benign ★★ 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/chrna7-p-val274ile (accessed [today's date]).

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