Is CHD7 p.Pro174Ser (c.520C>T) pathogenic?

CHD7 p.Pro174Ser (c.520C>T) is classified Uncertain significance in CHD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-06). AlphaMissense: likely benign (0.0655); Very rare (popmax 0.0011%, sas); Associated with CHARGE syndrome.

What condition is associated with CHD7 p.Pro174Ser (c.520C>T)?

CHD7 p.Pro174Ser (c.520C>T) is associated with CHARGE syndrome (ClinVar).

How common is CHD7 p.Pro174Ser (c.520C>T) in the general population?

CHD7 p.Pro174Ser (c.520C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CHD7 p.Pro174Ser (c.520C>T)?

AlphaMissense predicts likely benign (score 0.0655) — an in-silico prediction, not a clinical call.

CHD7 p.Pro174Ser

c.520C>T · rs2487265218 · VCV2036070

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

CHARGE syndrome

Computational evidence

Protein change
AlphaMissense	0.0655	likely benign
REVEL	0.101	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 3.3	GERP -0.38, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.84 · regional, not allelic
Overall
CADD	20.6	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

Grpmax group 0.0011% South Asian · 1/91,062 alleles

Overall 6.2e-05% 1/1,613,668 alleles · very rare exomes 1/1,461,378 · genomes 0/152,290 · 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.Pro174Ser
Coding: c.520C>T
MANE Select: NM_017780
dbSNP: rs2487265218
Type: single nucleotide variant
Location: chr8:60741952 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 174: 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

Similar variants

CHD7 p.Pro174= Likely benign ★★ same residue
CHD7 p.Pro174Leu Benign/Likely benign ★★ same residue
CHD7 p.Pro174fs 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

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-pro174ser (accessed [today's date]).

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