Is CHD7 p.Ser2559Phe (c.7676C>T) pathogenic?

CHD7 p.Ser2559Phe (c.7676C>T) is classified Uncertain significance in CHD7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-05-26). AlphaMissense: likely benign (0.3293); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHD7 p.Ser2559Phe (c.7676C>T)?

CHD7 p.Ser2559Phe (c.7676C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHD7 p.Ser2559Phe (c.7676C>T) in the general population?

CHD7 p.Ser2559Phe (c.7676C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CHD7 p.Ser2559Phe (c.7676C>T)?

AlphaMissense predicts likely benign (score 0.3293) — an in-silico prediction, not a clinical call.

CHD7 p.Ser2559Phe

c.7676C>T · VCV4868907

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3293 · ACMG-weighted

gnomAD v4.1

Rare

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

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3293	likely benign
REVEL	0.476	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 17 kb · p 7.3e-05 · regional, not allelic
Overall
CADD	28.3	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) · 1/1,179,900 alleles

Overall 6.2e-05% 1/1,614,032 alleles · very rare exomes 1/1,461,704 · genomes 0/152,328 · 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.Ser2559Phe
Coding: c.7676C>T
MANE Select: NM_017780
Type: single nucleotide variant
Location: chr8:60860971 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2559: a modified residue (phosphoserine)

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

Similar variants

CHD7 p.Arg1494Ter Pathogenic ★★ same condition
CHD7 p.Arg157Ter Pathogenic ★★ same condition
CHD7 p.Arg2024Ter Pathogenic ★★ same condition
CHD7 p.Arg2098Ter Pathogenic ★★ same condition
CHD7 p.Arg2428Ter Pathogenic ★★ same condition
CHD7 p.Arg312Ter Pathogenic ★★ same condition
CHD7 p.Cys1101Tyr Pathogenic/Likely pathogenic ★★ same condition
CHD7 p.Gln205Ter 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-ser2559phe (accessed [today's date]).

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