Is CHD7 p.Pro548Leu (c.1643C>T) pathogenic?

CHD7 p.Pro548Leu (c.1643C>T) is classified Conflicting classifications of pathogenicity in CHD7 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.1011); Very rare (popmax 0.00229%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHD7 p.Pro548Leu (c.1643C>T)?

CHD7 p.Pro548Leu (c.1643C>T) is associated with Inborn genetic diseases, CHARGE syndrome, hypogonadotropic hypogonadism 5 with or without anosmia (ClinVar).

How common is CHD7 p.Pro548Leu (c.1643C>T) in the general population?

CHD7 p.Pro548Leu (c.1643C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about CHD7 p.Pro548Leu (c.1643C>T)?

AlphaMissense predicts likely benign (score 0.1011) — an in-silico prediction, not a clinical call.

CHD7 p.Pro548Leu

c.1643C>T · rs778361949 · VCV909565

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1011 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1011	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; 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 7.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.84 · regional, not allelic
Overall
CADD	28.9	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 0.00229% European (non-Finnish) · 27/1,179,792 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00186% 30/1,613,596 alleles · very rare exomes 29/1,461,358 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,696
South Asian	0.0022%	45,499
Remaining individualsnot grpmax-eligible	0.0016%	62,462

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.Pro548Leu
Coding: c.1643C>T
MANE Select: NM_017780
dbSNP: rs778361949
Type: single nucleotide variant
Location: chr8:60743075 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 548: 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.Pro548= Conflicting classifications of pathogenicity ★ same residue
CHD7 p.Pro548Ser Benign ★ 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-pro548leu (accessed [today's date]).

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