Is CHIA p.Thr181Pro (c.541A>C) pathogenic?

CHIA p.Thr181Pro (c.541A>C) is classified Uncertain significance in CHIA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely pathogenic (0.6201); Absent from gnomAD v4.1.

How common is CHIA p.Thr181Pro (c.541A>C) in the general population?

CHIA p.Thr181Pro (c.541A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHIA p.Thr181Pro (c.541A>C)?

AlphaMissense predicts likely pathogenic (score 0.6201) — an in-silico prediction, not a clinical call.

CHIA p.Thr181Pro

c.541A>C · VCV4228102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6201 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6201	likely pathogenic
REVEL	0.388	indeterminate
SaProt	LLR -16.76	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -2.8, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,995 bp · p 0.014 · regional, not allelic
Overall
CADD	24.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHIA
Protein: p.Thr181Pro
Coding: c.541A>C
MANE Select: NM_201653
Type: single nucleotide variant
Location: chr1:111317741 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.65 · 8 PDB
Residue 181: a disulfide bond; the gh18 domain; a β-strand

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

Similar variants

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
CHIA p.Ala182Thr 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/chia-p-thr181pro (accessed [today's date]).

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