Is CHD7 p.Pro703= (c.2109T>G) pathogenic?

CHD7 p.Pro703= (c.2109T>G) is classified Likely benign in CHD7 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-04). Ultra-rare (popmax 0.0284%, amr); Associated with CHARGE syndrome.

What condition is associated with CHD7 p.Pro703= (c.2109T>G)?

CHD7 p.Pro703= (c.2109T>G) is associated with CHARGE syndrome, hypogonadotropic hypogonadism 5 with or without anosmia (ClinVar).

How common is CHD7 p.Pro703= (c.2109T>G) in the general population?

CHD7 p.Pro703= (c.2109T>G) is ultra-rare (popmax 0.0284%, amr) (gnomAD).

CHD7 p.Pro703=

c.2109T>G · rs192950146 · VCV701724

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0284%, amr)

Conditions

CHARGE syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.29	GERP -2.2, phastCons 0.99
Overall
CADD	8.185	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0284% Admixed American · 17/59,882 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0148%

Overall 0.00136% 22/1,613,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0284%	3,522
Remaining individualsnot grpmax-eligible	0.00641%	15,609
African / African-American	0.00134%	74,906

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.Pro703=
Coding: c.2109T>G
MANE Select: NM_017780
dbSNP: rs192950146
Type: single nucleotide variant
Location: chr8:60794998 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 703: the 'disordered' region

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

Also linked: hypogonadotropic hypogonadism 5 with or without anosmia

Similar variants

CHD7 p.Pro703Thr Conflicting classifications of pathogenicity ★ ⚠ 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
CHD7 c.2836-2A>T Pathogenic ★★ same condition
CHD7 c.2957+2T>C 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-pro703 (accessed [today's date]).

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