Is CHIC2 p.Lys109Arg (c.326A>G) pathogenic?

CHIC2 p.Lys109Arg (c.326A>G) is classified Uncertain significance in CHIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-16). AlphaMissense: likely benign (0.1276); Very rare (popmax 0.00113%, nfe).

How common is CHIC2 p.Lys109Arg (c.326A>G) in the general population?

CHIC2 p.Lys109Arg (c.326A>G) is very rare (popmax 0.00113%, nfe) (gnomAD).

What do computational predictors say about CHIC2 p.Lys109Arg (c.326A>G)?

AlphaMissense predicts likely benign (score 0.1276) — an in-silico prediction, not a clinical call.

CHIC2 p.Lys109Arg

c.326A>G · rs777419410 · VCV2515174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1276 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00113%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1276	likely benign
REVEL	0.161	moderately benign-leaning
SaProt	LLR -8.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 54 kb · p 8.1e-05 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00113% European (non-Finnish) · 13/1,146,974 alleles

Filtering AF 0.000632% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000487%

Overall 0.000841% 13/1,546,554 alleles · very rare

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: CHIC2
Protein: p.Lys109Arg
Coding: c.326A>G
MANE Select: NM_012110
dbSNP: rs777419410
Type: single nucleotide variant
Location: chr4:54048959 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI 0.18 (gnomAD)
Structure: AlphaFold pLDDT 84.67 · 1 PDB

Full CHIC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHIC2 p.Arg163Gln Uncertain significance ★ ⚠ same type
CHIC2 p.Arg16Gln Uncertain significance ★ ⚠ same type
CHIC2 p.Glu20Ala Uncertain significance ★ ⚠ same type
CHIC2 p.Ile151Met Uncertain significance ★ ⚠ same type
CHIC2 p.Leu75Val Uncertain significance ★ ⚠ same type
CHIC2 p.Pro160Gln Uncertain significance ★ ⚠ same type
CHIC2 p.Ser137Arg Uncertain significance ★ ⚠ same type
CHIC2 p.Thr39Ile 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/chic2-p-lys109arg (accessed [today's date]).

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