Is CHD7 p.Ser699Arg (c.2097T>G) pathogenic?

CHD7 p.Ser699Arg (c.2097T>G) is classified Uncertain significance in CHD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). AlphaMissense: likely pathogenic (0.8642); Very rare (popmax 8.48e-05%, nfe); Associated with hypogonadotropic hypogonadism 5 with or without anosmia.

What condition is associated with CHD7 p.Ser699Arg (c.2097T>G)?

CHD7 p.Ser699Arg (c.2097T>G) is associated with hypogonadotropic hypogonadism 5 with or without anosmia (ClinVar).

How common is CHD7 p.Ser699Arg (c.2097T>G) in the general population?

CHD7 p.Ser699Arg (c.2097T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CHD7 p.Ser699Arg (c.2097T>G)?

AlphaMissense predicts likely pathogenic (score 0.8642) — an in-silico prediction, not a clinical call.

CHD7 p.Ser699Arg

c.2097T>G · rs767027265 · VCV911722

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hypogonadotropic hypogonadism 5 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.8642	likely pathogenic
REVEL	0.223	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.84 · regional, not allelic
Overall
CADD	24.1	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 8.48e-05% European (non-Finnish) · 1/1,179,264 alleles

Overall 6.2e-05% 1/1,612,042 alleles · very rare exomes 1/1,459,814 · genomes 0/152,228 · joint denominator

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.Ser699Arg
Coding: c.2097T>G
MANE Select: NM_017780
dbSNP: rs767027265
Type: single nucleotide variant
Location: chr8:60794986 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 699: the 'disordered' region; a UniProt-annotated variant site (in charges; uncertain significance)

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

Disease context

hypogonadotropic hypogonadism 5 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHD7 p.Ser699Gly Pathogenic/Likely pathogenic ★★ ⚠ same residue
CHD7 p.Ser699Asn Uncertain significance ★★ same residue
CHD7 c.4353+1G>T Pathogenic ★★ same condition
CHD7 c.5405-17G>A Pathogenic ★★ same condition
CHD7 c.5405-7G>A Pathogenic ★★ same condition
CHD7 p.Arg1069Ter Pathogenic ★★ same condition
CHD7 p.Arg1677Ter Pathogenic ★★ same condition
CHD7 p.Arg2053Ter 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-ser699arg (accessed [today's date]).

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