Is CHD7 p.His203Arg (c.608A>G) pathogenic?

CHD7 p.His203Arg (c.608A>G) is classified Conflicting classifications of pathogenicity in CHD7 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-25). AlphaMissense: likely benign (0.2457); Ultra-rare (popmax 0.0177%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHD7 p.His203Arg (c.608A>G)?

CHD7 p.His203Arg (c.608A>G) is associated with Inborn genetic diseases, CHARGE syndrome, hypogonadotropic hypogonadism 5 with or without anosmia (ClinVar).

How common is CHD7 p.His203Arg (c.608A>G) in the general population?

CHD7 p.His203Arg (c.608A>G) is ultra-rare (popmax 0.0177%, nfe) (gnomAD).

What do computational predictors say about CHD7 p.His203Arg (c.608A>G)?

AlphaMissense predicts likely benign (score 0.2457) — an in-silico prediction, not a clinical call.

CHD7 p.His203Arg

c.608A>G · rs375277827 · VCV566957

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2457 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2457	likely benign
REVEL	0.283	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 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.84 · regional, not allelic
Overall
CADD	22.8	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 0.0177% European (non-Finnish) · 209/1,179,884 alleles

Filtering AF 0.0157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.015%

Overall 0.0132% 213/1,613,770 alleles · ultra-rare exomes 200/1,461,598 · genomes 13/152,172 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0177%	5,645
Remaining individualsnot grpmax-eligible	0.0032%	31,232
African / African-American	0.00267%	37,452

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.His203Arg
Coding: c.608A>G
MANE Select: NM_017780
dbSNP: rs375277827
Type: single nucleotide variant
Location: chr8:60742040 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 203: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: CHARGE syndrome hypogonadotropic hypogonadism 5 with or without anosmia

Similar variants

CHD7 p.His203Gln Uncertain significance ★ ⚠ 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-his203arg (accessed [today's date]).

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