Is CHIA p.Arg35Trp (c.103C>T) pathogenic?

CHIA p.Arg35Trp (c.103C>T) is classified Benign in CHIA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-15). AlphaMissense: ambiguous (0.3402); Low-frequency (popmax 4.49%, afr).

How common is CHIA p.Arg35Trp (c.103C>T) in the general population?

CHIA p.Arg35Trp (c.103C>T) is low-frequency (popmax 4.49%, afr) (gnomAD).

What do computational predictors say about CHIA p.Arg35Trp (c.103C>T)?

AlphaMissense predicts ambiguous (score 0.3402) — an in-silico prediction, not a clinical call.

CHIA p.Arg35Trp

c.103C>T · rs61752461 · VCV769525

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3402 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.49%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3402	ambiguous
REVEL	0.212	benign-leaning
SaProt	LLR -13.48	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.26 · evaluated, not missing
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	16.53	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 4.49% African / African-American · 3,366/74,992 alleles

Filtering AF 4.36% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.31%

Overall 0.234% 3,779/1,614,084 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.49%	22
Remaining individualsnot grpmax-eligible	0.28%	357
Admixed American	0.27%	370
Middle Eastern	0.214%	466
South Asian	0.00988%	10,119
East Asian	0.00668%	14,962
European (non-Finnish)	0.00424%	23,600
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606

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.Arg35Trp
Coding: c.103C>T
MANE Select: NM_201653
dbSNP: rs61752461
Type: single nucleotide variant
Location: chr1:111312237 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.65 · 8 PDB
Residue 35: a disulfide bond; the gh18 domain

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

Similar variants

CHIA p.Arg35Gln Uncertain significance ★ ⚠ same residue
CHIA p.Ala295Thr Benign/Likely benign ★★ same type
CHIA p.Ala57Thr Likely 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-arg35trp (accessed [today's date]).

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