Is CHD2 p.Leu876Phe (c.2628G>T) pathogenic?

CHD2 p.Leu876Phe (c.2628G>T) is classified Likely pathogenic in CHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-25). AlphaMissense: likely pathogenic (0.9992); Absent from gnomAD v4.1; Associated with CHD2-related disorder.

What condition is associated with CHD2 p.Leu876Phe (c.2628G>T)?

CHD2 p.Leu876Phe (c.2628G>T) is associated with CHD2-related disorder (ClinVar).

How common is CHD2 p.Leu876Phe (c.2628G>T) in the general population?

CHD2 p.Leu876Phe (c.2628G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHD2 p.Leu876Phe (c.2628G>T)?

AlphaMissense predicts likely pathogenic (score 0.9992) — an in-silico prediction, not a clinical call.

CHD2 p.Leu876Phe

c.2628G>T · rs772889877 · VCV2631550

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9992 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CHD2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9992	likely pathogenic ✓ concordant with ClinVar · top 3% in CHD2
REVEL	0.76	pathogenic-leaning
SaProt	LLR -12.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 2, phastCons 1
Regional constraint	o/e 0.16	constrained · MANE · 4,305 bp · p 1.3e-19 · regional, not allelic
Overall
CADD	28.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHD2
Protein: p.Leu876Phe
Coding: c.2628G>T
MANE Select: NM_001271
dbSNP: rs772889877
Type: single nucleotide variant
Location: chr15:92978284 (GRCh38)
Gene constraint: LOEUF 0.174 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 60.81
Residue 876: the helicase c-terminal domain; a UniProt-annotated variant site (in dee94); a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy; uncertain significance)

Full CHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CHD2-related disorder

Similar variants

CHD2 p.Leu876= Likely benign ★★ same residue
CHD2 p.Arg1313Ter Pathogenic ★★ same condition
CHD2 p.Arg1546Ter Pathogenic ★★ same condition
CHD2 p.Arg224Ter Pathogenic/Likely pathogenic ★★ same condition
CHD2 p.Arg466Ter Pathogenic ★★ same condition
CHD2 p.Gln1641Ter Pathogenic/Likely pathogenic ★★ same condition
CHD2 p.Tyr1700Ter Pathogenic ★★ same condition
CHD2 c.2352+1G>A Likely pathogenic ★ same condition

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/chd2-p-leu876phe (accessed [today's date]).

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