Is CHD4 p.Pro516= (c.1548C>T) pathogenic?

CHD4 p.Pro516= (c.1548C>T) is classified Benign in CHD4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 16.2%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Sifrim-Hitz-Weiss syndrome.

What condition is associated with CHD4 p.Pro516= (c.1548C>T)?

CHD4 p.Pro516= (c.1548C>T) is associated with Sifrim-Hitz-Weiss syndrome (ClinVar).

How is CHD4-related neurodevelopmental disorder inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CHD4 p.Pro516=

Q: How common is CHD4 p.Pro516= (c.1548C>T) in the general population?

CHD4 p.Pro516= (c.1548C>T) is common (popmax 16.2%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1548C>T · rs11539543 · VCV1209740

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 16.2%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

Sifrim-Hitz-Weiss syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.74	GERP -3.7, phastCons 1
Overall
CADD	7.93	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 16.2% European (non-Finnish) · 190,618/1,179,754 alleles

Filtering AF 16.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.1%

Overall 14.9% 240,966/1,613,668 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	16.2%	6
Finnishnot grpmax-eligible	16.1%	6
South Asian	15%	7
African / African-American	13.6%	7
Remaining individualsnot grpmax-eligible	13.5%	7
Middle Eastern	12%	8
Amishnot grpmax-eligible	11%	9
Ashkenazi Jewishnot grpmax-eligible	9.19%	11
Admixed American	6.85%	15
East Asian	0.176%	568

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: CHD4
Protein: p.Pro516=
Coding: c.1548C>T
MANE Select: NM_001273
dbSNP: rs11539543
Type: single nucleotide variant
Location: chr12:6598360 (GRCh38)
Gene constraint: LOEUF 0.192 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 65.41 · 12 PDB
Residue 516: the chromo 1 domain; an α-helix; the 'disordered' region

Full CHD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Sifrim-Hitz-Weiss syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CHD4-related neurodevelopmental disorder (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy

Similar variants

CHD4 p.Pro516Leu Uncertain significance ★★ ⚠ same residue
CHD4 p.Arg1068His Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1173Gln Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1173Trp Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1177Cys Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1183Cys Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1183His Pathogenic/Likely pathogenic ★★ same condition
CHD4 p.Arg1340Cys 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/chd4-p-pro516 (accessed [today's date]).

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