Is CHD1 p.Ser216Phe (c.647C>T) pathogenic?

CHD1 p.Ser216Phe (c.647C>T) is classified Uncertain significance in CHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-10-12). AlphaMissense: likely benign (0.3039); Very rare (popmax 8.48e-05%, nfe).

How common is CHD1 p.Ser216Phe (c.647C>T) in the general population?

CHD1 p.Ser216Phe (c.647C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CHD1 p.Ser216Phe (c.647C>T)?

AlphaMissense predicts likely benign (score 0.3039) — an in-silico prediction, not a clinical call.

CHD1 p.Ser216Phe

c.647C>T · VCV4971587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3039 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3039	likely benign
REVEL	0.491	indeterminate
SaProt	LLR -11.17	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 26 kb · p 0.65 · regional, not allelic
Overall
CADD	28.3	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 8.48e-05% European (non-Finnish) · 1/1,179,610 alleles

Overall 6.2e-05% 1/1,612,498 alleles · very rare exomes 1/1,460,450 · genomes 0/152,048 · 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: CHD1
Protein: p.Ser216Phe
Coding: c.647C>T
MANE Select: NM_001270
Type: single nucleotide variant
Location: chr5:98901023 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.63 · 18 PDB
Residue 216: a modified residue (phosphoserine); the 'disordered' region

Full CHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHD1 p.Ser216Cys Uncertain significance ★ ⚠ same residue
CHD1 p.Ser216Thr Uncertain significance ★ ⚠ same residue
CHD1 p.Arg1378Gly Uncertain significance ★★ ⚠ same type
CHD1 p.Arg1659Thr Uncertain significance ★★ ⚠ same type
CHD1 p.Arg1676Gly Uncertain significance ★★ ⚠ same type
CHD1 p.Arg1708Gln Uncertain significance ★★ same type
CHD1 p.Arg1708Trp Uncertain significance ★★ ⚠ same type
CHD1 p.Arg233His 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/chd1-p-ser216phe (accessed [today's date]).

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