Is CHD7 p.Leu485Pro (c.1454T>C) pathogenic?

CHD7 p.Leu485Pro (c.1454T>C) is classified Conflicting classifications of pathogenicity in CHD7 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-10-03). AlphaMissense: likely benign (0.0691); Very rare (popmax 0.00669%, eas); Associated with CHARGE syndrome.

What condition is associated with CHD7 p.Leu485Pro (c.1454T>C)?

CHD7 p.Leu485Pro (c.1454T>C) is associated with CHARGE syndrome (ClinVar).

How common is CHD7 p.Leu485Pro (c.1454T>C) in the general population?

CHD7 p.Leu485Pro (c.1454T>C) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about CHD7 p.Leu485Pro (c.1454T>C)?

AlphaMissense predicts likely benign (score 0.0691) — an in-silico prediction, not a clinical call.

CHD7 p.Leu485Pro

c.1454T>C · rs1313748646 · VCV939998

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0691 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

CHARGE syndrome

Computational evidence

Protein change
AlphaMissense	0.0691	likely benign
REVEL	0.223	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 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.84 · regional, not allelic
Overall
CADD	24.6	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 0.00669% East Asian · 3/44,846 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.000822% 12/1,460,010 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,949
European (non-Finnish)	0.000763%	131,003

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.Leu485Pro
Coding: c.1454T>C
MANE Select: NM_017780
dbSNP: rs1313748646
Type: single nucleotide variant
Location: chr8:60742886 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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 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
CHD7 c.3202-3T>G 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-leu485pro (accessed [today's date]).

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