Is CHD7 p.Phe765Leu (c.2295C>G) pathogenic?

CHD7 p.Phe765Leu (c.2295C>G) is classified Conflicting classifications of pathogenicity in CHD7 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-15). AlphaMissense: likely pathogenic (0.9776); Very rare (popmax 0.00934%, afr); Associated with Inborn genetic diseases.

What condition is associated with CHD7 p.Phe765Leu (c.2295C>G)?

CHD7 p.Phe765Leu (c.2295C>G) is associated with Inborn genetic diseases, CHARGE syndrome, hypogonadotropic hypogonadism 5 with or without anosmia (ClinVar).

How common is CHD7 p.Phe765Leu (c.2295C>G) in the general population?

CHD7 p.Phe765Leu (c.2295C>G) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about CHD7 p.Phe765Leu (c.2295C>G)?

AlphaMissense predicts likely pathogenic (score 0.9776) — an in-silico prediction, not a clinical call.

CHD7 p.Phe765Leu

c.2295C>G · rs200006916 · VCV1789158

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9776 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9776	likely pathogenic
REVEL	0.182	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.99, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.84 · regional, not allelic
Overall
CADD	22.7	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 0.00934% African / African-American · 7/74,920 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000496% 8/1,613,708 alleles · very rare exomes 7/1,461,528 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,703
Admixed American	0.00167%	59,984

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.Phe765Leu
Coding: c.2295C>G
MANE Select: NM_017780
dbSNP: rs200006916
Type: single nucleotide variant
Location: chr8:60800444 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 765: 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.Phe765fs Pathogenic ★ 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-phe765leu (accessed [today's date]).

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