Is CHD7 p.Pro515Ser (c.1543C>T) pathogenic?

CHD7 p.Pro515Ser (c.1543C>T) is classified Uncertain significance in CHD7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-25). AlphaMissense: likely benign (0.0594); Absent from gnomAD v4.1; Associated with hypogonadotropic hypogonadism 5 with or without anosmia.

What condition is associated with CHD7 p.Pro515Ser (c.1543C>T)?

CHD7 p.Pro515Ser (c.1543C>T) is associated with hypogonadotropic hypogonadism 5 with or without anosmia, CHARGE syndrome (ClinVar).

How common is CHD7 p.Pro515Ser (c.1543C>T) in the general population?

CHD7 p.Pro515Ser (c.1543C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHD7 p.Pro515Ser (c.1543C>T)?

AlphaMissense predicts likely benign (score 0.0594) — an in-silico prediction, not a clinical call.

CHD7 p.Pro515Ser

c.1543C>T · rs1210884047 · VCV1369874

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0594 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

hypogonadotropic hypogonadism 5 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.0594	likely benign
REVEL	0.041	moderately 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 4	GERP -0.13, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.84 · regional, not allelic
Overall
CADD	20.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHD7
Protein: p.Pro515Ser
Coding: c.1543C>T
MANE Select: NM_017780
dbSNP: rs1210884047
Type: single nucleotide variant
Location: chr8:60742975 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 515: the 'disordered' region

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

Also linked: CHARGE syndrome

Similar variants

CHD7 p.Pro515Thr Uncertain significance ★★ ⚠ same residue
CHD7 p.Pro515Ala 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

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-pro515ser (accessed [today's date]).

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