Is CHD8 p.Arg2056Pro (c.6167G>C) pathogenic?

CHD8 p.Arg2056Pro (c.6167G>C) is classified Uncertain significance in CHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-07). AlphaMissense: likely benign (0.1292); Very rare (popmax 0.005%, amr).

How common is CHD8 p.Arg2056Pro (c.6167G>C) in the general population?

CHD8 p.Arg2056Pro (c.6167G>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CHD8 p.Arg2056Pro (c.6167G>C)?

AlphaMissense predicts likely benign (score 0.1292) — an in-silico prediction, not a clinical call.

CHD8 p.Arg2056Pro

c.6167G>C · rs572070685 · VCV2996287

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1292 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1292	likely benign
REVEL	0.505	indeterminate
SaProt	LLR -4.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.49 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.1	GERP 0.33, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 2,499 bp · p 8e-07 · regional, not allelic
Overall
CADD	19.94	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 0.005% Admixed American · 3/60,004 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,613,908 alleles · very rare exomes 2/1,461,662 · genomes 1/152,246 · joint denominator

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: CHD8
Protein: p.Arg2056Pro
Coding: c.6167G>C
MANE Select: NM_001170629
dbSNP: rs572070685
Type: single nucleotide variant
Location: chr14:21393628 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 2056: the 'interaction with fam124b' region; the 'disordered' region

Full CHD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHD8 p.Arg2056Gln Likely benign ★★ same residue
CHD8 p.Arg2056= Benign ★ same residue
CHD8 p.Arg2056Trp Likely benign ★ same residue
CHD8 c.3882+1G>A Pathogenic/Likely pathogenic ★★ same type
CHD8 p.Arg1188Ter Pathogenic ★★ same type
CHD8 p.Arg1242Gln Likely pathogenic ★★ same type
CHD8 p.Arg1242Ter Pathogenic ★★ same type
CHD8 p.Arg1245Ter Pathogenic ★★ 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/chd8-p-arg2056pro (accessed [today's date]).

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