Is CHD6 p.Pro1813Arg (c.5438C>G) pathogenic?

CHD6 p.Pro1813Arg (c.5438C>G) is classified Uncertain significance in CHD6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). AlphaMissense: likely benign (0.1046); Ultra-rare (popmax 0.0167%, amr).

How common is CHD6 p.Pro1813Arg (c.5438C>G) in the general population?

CHD6 p.Pro1813Arg (c.5438C>G) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about CHD6 p.Pro1813Arg (c.5438C>G)?

AlphaMissense predicts likely benign (score 0.1046) — an in-silico prediction, not a clinical call.

CHD6 p.Pro1813Arg

c.5438C>G · VCV4002138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1046 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1046	likely benign
REVEL	0.183	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 0.63, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 16 kb · p 0.46 · regional, not allelic
Overall
CADD	20.8	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/59,938 alleles

Filtering AF 0.00901% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00682%

Overall 0.00089% 13/1,461,052 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,994
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	8.48e-05%	1,179,686

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: CHD6
Protein: p.Pro1813Arg
Coding: c.5438C>G
MANE Select: NM_032221
Type: single nucleotide variant
Location: chr20:41421197 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 (gnomAD)

Full CHD6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHD6 c.1858-19G>A Benign ★★ same type
CHD6 c.554+5G>A Benign/Likely benign ★★ same type
CHD6 c.852+4T>C Benign ★★ same type
CHD6 p.Ala1205Gly Benign ★★ same type
CHD6 p.Arg2389Cys Benign ★★ same type
CHD6 p.Glu1271= Benign ★★ same type
CHD6 p.Glu2404Gln Benign ★★ same type
CHD6 p.Gly1519Asp 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/chd6-p-pro1813arg (accessed [today's date]).

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