Is CHIA p.Arg116Cys (c.346C>T) pathogenic?

CHIA p.Arg116Cys (c.346C>T) is classified Uncertain significance in CHIA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-13). AlphaMissense: likely benign (0.3172); Ultra-rare (popmax 0.0242%, sas).

How common is CHIA p.Arg116Cys (c.346C>T) in the general population?

CHIA p.Arg116Cys (c.346C>T) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

What do computational predictors say about CHIA p.Arg116Cys (c.346C>T)?

AlphaMissense predicts likely benign (score 0.3172) — an in-silico prediction, not a clinical call.

CHIA p.Arg116Cys

c.346C>T · rs543573136 · VCV2284212

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3172 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3172	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -13.17	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 -2.5	GERP 1.9
Regional constraint	o/e 1.10	unconstrained · MANE · 9,995 bp · p 0.014 · regional, not allelic
Overall
CADD	25.6	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 0.0242% South Asian · 22/91,020 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.00329% 53/1,612,752 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,137
Admixed American	0.00833%	12,002
African / African-American	0.00667%	14,996
Remaining individualsnot grpmax-eligible	0.00321%	31,195
East Asian	0.00223%	44,866
European (non-Finnish)	0.00153%	65,550

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.Arg116Cys
Coding: c.346C>T
MANE Select: NM_201653
dbSNP: rs543573136
Type: single nucleotide variant
Location: chr1:111315301 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.65 · 8 PDB
Residue 116: 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.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-arg116cys (accessed [today's date]).

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