Is CHD5 p.Ser1539Pro (c.4615T>C) pathogenic?

CHD5 p.Ser1539Pro (c.4615T>C) is classified Benign in CHD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-11). AlphaMissense: likely benign (0.0529); Common (popmax 99.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with parenti-mignot neurodevelopmental syndrome.

What condition is associated with CHD5 p.Ser1539Pro (c.4615T>C)?

CHD5 p.Ser1539Pro (c.4615T>C) is associated with parenti-mignot neurodevelopmental syndrome (ClinVar).

What do computational predictors say about CHD5 p.Ser1539Pro (c.4615T>C)?

AlphaMissense predicts likely benign (score 0.0529) — an in-silico prediction, not a clinical call.

CHD5 p.Ser1539Pro

Q: How common is CHD5 p.Ser1539Pro (c.4615T>C) in the general population?

CHD5 p.Ser1539Pro (c.4615T>C) is common (popmax 99.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.4615T>C · rs2843493 · VCV2585658

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0529 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 99.6%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

parenti-mignot neurodevelopmental syndrome

Computational evidence

Protein change
AlphaMissense	0.0529	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -5.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -2.3, phastCons 1
Overall
CADD	17.87	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 99.6% East Asian · 44,459/44,638 alleles

Filtering AF 98.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.5%

Overall 59.7% 961,888/1,611,694 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	99.6%	1
South Asian	77.3%	1
Finnishnot grpmax-eligible	70%	1
Ashkenazi Jewishnot grpmax-eligible	69.2%	1
Middle Eastern	63.4%	2
Remaining individualsnot grpmax-eligible	61.8%	2
African / African-American	59.3%	2
Admixed American	58.6%	2
Amishnot grpmax-eligible	56.1%	2
European (non-Finnish)	56%	2

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: CHD5
Protein: p.Ser1539Pro
Coding: c.4615T>C
MANE Select: NM_015557
dbSNP: rs2843493
Type: single nucleotide variant
Location: chr1:6124032 (GRCh38)
Structure: AlphaFold pLDDT 78.15 · 4 PDB

Full CHD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

parenti-mignot neurodevelopmental syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHD5 c.4171+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD5 p.Arg193Trp Pathogenic/Likely pathogenic ★★ same condition
CHD5 c.79+5G>A Uncertain significance ★★ same condition
CHD5 p.Ala215Val Uncertain significance ★★ same condition
CHD5 p.Asp23Asn Uncertain significance ★★ ⚠ same condition
CHD5 p.Lys818Arg Uncertain significance ★★ ⚠ same condition
CHD5 p.Pro1215Leu Uncertain significance ★★ ⚠ same condition
CHD5 p.Pro1409Ser Uncertain significance ★★ ⚠ 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/chd5-p-ser1539pro (accessed [today's date]).

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