Is CHIA p.Glu305Val (c.914A>T) pathogenic?

CHIA p.Glu305Val (c.914A>T) is classified Uncertain significance in CHIA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.9461); Ultra-rare (popmax 0.0112%, nfe).

How common is CHIA p.Glu305Val (c.914A>T) in the general population?

CHIA p.Glu305Val (c.914A>T) is ultra-rare (popmax 0.0112%, nfe) (gnomAD).

What do computational predictors say about CHIA p.Glu305Val (c.914A>T)?

AlphaMissense predicts likely pathogenic (score 0.9461) — an in-silico prediction, not a clinical call.

CHIA p.Glu305Val

c.914A>T · VCV4653374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9461 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9461	likely pathogenic · top 2% in CHIA
REVEL	0.71	pathogenic-leaning
SaProt	LLR -15.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,995 bp · p 0.014 · regional, not allelic
Overall
CADD	25.3	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 0.0112% European (non-Finnish) · 132/1,179,202 alleles

Filtering AF 0.00961% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00843% 136/1,612,498 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0112%	8,933
Remaining individualsnot grpmax-eligible	0.00481%	20,800
African / African-American	0.00134%	74,896

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: CHIA
Protein: p.Glu305Val
Coding: c.914A>T
MANE Select: NM_201653
Type: single nucleotide variant
Location: chr1:111318677 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.65 · 8 PDB
Residue 305: a disulfide bond; the gh18 domain; an α-helix

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

Similar variants

CHIA p.Glu305Lys Uncertain significance ★ ⚠ same residue
CHIA p.Ala295Thr Benign/Likely benign ★★ same type
CHIA p.Ala57Thr Likely benign ★★ ⚠ same type
CHIA p.Arg35Trp Benign ★★ ⚠ same type
CHIA p.Gly317Glu Benign ★★ same type
CHIA p.Gly356= Benign ★★ same type
CHIA p.Ile272= Benign ★★ same type
CHIA p.Lys251= 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/chia-p-glu305val (accessed [today's date]).

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