Is CHD7 p.Arg2491Cys (c.7471C>T) pathogenic?

CHD7 p.Arg2491Cys (c.7471C>T) is classified Conflicting classifications of pathogenicity in CHD7 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-01). AlphaMissense: likely benign (0.0935); Ultra-rare (popmax 0.0165%, mid); Associated with CHARGE syndrome.

What condition is associated with CHD7 p.Arg2491Cys (c.7471C>T)?

CHD7 p.Arg2491Cys (c.7471C>T) is associated with CHARGE syndrome (ClinVar).

How common is CHD7 p.Arg2491Cys (c.7471C>T) in the general population?

CHD7 p.Arg2491Cys (c.7471C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CHD7 p.Arg2491Cys (c.7471C>T)?

AlphaMissense predicts likely benign (score 0.0935) — an in-silico prediction, not a clinical call.

CHD7 p.Arg2491Cys

c.7471C>T · rs755492299 · VCV2061839

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0935 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

CHARGE syndrome

Computational evidence

Protein change
AlphaMissense	0.0935	likely benign
REVEL	0.244	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 7.3e-05 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0018% 29/1,614,036 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.00446%	22,441
Remaining individualsnot grpmax-eligible	0.0032%	31,242
South Asian	0.0022%	45,543
European (non-Finnish)	0.00178%	56,186
African / African-American	0.00133%	75,054

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: CHD7
Protein: p.Arg2491Cys
Coding: c.7471C>T
MANE Select: NM_017780
dbSNP: rs755492299
Type: single nucleotide variant
Location: chr8:60856751 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2491: a UniProt-annotated variant site (in)

Full CHD7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CHARGE syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHD7 p.Arg2491His Benign/Likely benign ★★ same residue
CHD7 p.Arg2491Ser Uncertain significance ★ ⚠ same residue
CHD7 p.Arg2491= Likely benign ★ same residue
CHD7 c.2097-2A>G Pathogenic ★★ same condition
CHD7 c.2238+1G>A Pathogenic ★★ same condition
CHD7 c.2377-1G>A Likely pathogenic ★★ same condition
CHD7 c.2613+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD7 c.2836-1G>A Pathogenic/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/chd7-p-arg2491cys (accessed [today's date]).

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