Is CHD5 p.Ala756Val (c.2267C>T) pathogenic?

CHD5 p.Ala756Val (c.2267C>T) is classified Uncertain significance in CHD5 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-14). AlphaMissense: likely pathogenic (0.8447); Ultra-rare (popmax 0.0203%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CHD5 p.Ala756Val (c.2267C>T)?

CHD5 p.Ala756Val (c.2267C>T) is associated with Inborn genetic diseases, parenti-mignot neurodevelopmental syndrome (ClinVar).

How common is CHD5 p.Ala756Val (c.2267C>T) in the general population?

CHD5 p.Ala756Val (c.2267C>T) is ultra-rare (popmax 0.0203%, nfe) (gnomAD).

What do computational predictors say about CHD5 p.Ala756Val (c.2267C>T)?

AlphaMissense predicts likely pathogenic (score 0.8447) — an in-silico prediction, not a clinical call.

CHD5 p.Ala756Val

c.2267C>T · rs144145989 · VCV2224371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8447 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0203%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8447	likely pathogenic
REVEL	0.682	pathogenic-leaning
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Overall
CADD	27.4	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 0.0203% European (non-Finnish) · 239/1,178,564 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0173%

Overall 0.0162% 261/1,612,348 alleles · ultra-rare exomes 242/1,460,128 · genomes 19/152,220 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,277
European (non-Finnish)grpmax	0.0203%	4,931
Remaining individualsnot grpmax-eligible	0.00481%	20,801
South Asian	0.00329%	30,357
African / African-American	0.00267%	37,447
Admixed American	0.00167%	59,986

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala756Val
Coding: c.2267C>T
MANE Select: NM_015557
dbSNP: rs144145989
Type: single nucleotide variant
Location: chr1:6142297 (GRCh38)
Structure: AlphaFold pLDDT 78.15 · 4 PDB

Full CHD5 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: parenti-mignot neurodevelopmental syndrome

Similar variants

CHD5 p.Ala756Thr Uncertain significance ★ ⚠ same residue
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.Ala1435Thr Uncertain significance ★★ ⚠ same condition
CHD5 p.Ala1446Ser Uncertain significance ★★ ⚠ same condition
CHD5 p.Ala215Val Uncertain significance ★★ same condition
CHD5 p.Arg1337Cys 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-ala756val (accessed [today's date]).

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