Is CHD9 p.Pro214Ser (c.640C>T) pathogenic?

CHD9 p.Pro214Ser (c.640C>T) is classified Uncertain significance in CHD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0589); Ultra-rare (popmax 0.0283%, amr).

How common is CHD9 p.Pro214Ser (c.640C>T) in the general population?

CHD9 p.Pro214Ser (c.640C>T) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about CHD9 p.Pro214Ser (c.640C>T)?

AlphaMissense predicts likely benign (score 0.0589) — an in-silico prediction, not a clinical call.

CHD9 p.Pro214Ser

c.640C>T · VCV4002182

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0589 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0589	likely benign
REVEL	0.198	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.15	GERP -0.56
Regional constraint	o/e 0.96	unconstrained · MANE · 75 kb · p 0.29 · regional, not allelic
Overall
CADD	8.752	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0283% Admixed American · 17/60,018 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.00118% 19/1,613,818 alleles · ultra-rare exomes 19/1,461,508 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0283%	3,530
Remaining individualsnot grpmax-eligible	0.0016%	62,482
South Asian	0.0011%	91,080

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: CHD9
Protein: p.Pro214Ser
Coding: c.640C>T
MANE Select: NM_001308319
Type: single nucleotide variant
Location: chr16:53156729 (GRCh38)
Gene constraint: LOEUF 0.309 · pLI 1.00 (gnomAD)
Residue 214: the 'disordered' region

Full CHD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHD9 c.6620-2A>C Uncertain significance ★ same type
CHD9 p.Ala1363Thr Uncertain significance ★ ⚠ same type
CHD9 p.Ala1408Val Uncertain significance ★ ⚠ same type
CHD9 p.Ala1537Thr Uncertain significance ★ same type
CHD9 p.Ala167Val Uncertain significance ★ same type
CHD9 p.Ala1724Gly Uncertain significance ★ same type
CHD9 p.Ala1742Val Uncertain significance ★ same type
CHD9 p.Ala1938Thr Uncertain significance ★ ⚠ same type

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/chd9-p-pro214ser (accessed [today's date]).

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