Is CHD1 p.Ser158Phe (c.473C>T) pathogenic?

CHD1 p.Ser158Phe (c.473C>T) is classified Uncertain significance in CHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-18). AlphaMissense: likely benign (0.1625); Ultra-rare (popmax 0.0379%, eas).

How common is CHD1 p.Ser158Phe (c.473C>T) in the general population?

CHD1 p.Ser158Phe (c.473C>T) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

What do computational predictors say about CHD1 p.Ser158Phe (c.473C>T)?

AlphaMissense predicts likely benign (score 0.1625) — an in-silico prediction, not a clinical call.

CHD1 p.Ser158Phe

c.473C>T · rs368819719 · VCV2568460

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1625 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1625	likely benign
REVEL	0.597	indeterminate
SaProt	LLR -10.69	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	28.5	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 0.0379% East Asian · 17/44,826 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.0044% 71/1,612,598 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0769%	1,301
East Asiangrpmax	0.0379%	2,637
Admixed American	0.0067%	14,919
South Asian	0.0011%	90,670
European (non-Finnish)	8.48e-05%	1,179,690

Remaining individuals 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: CHD1
Protein: p.Ser158Phe
Coding: c.473C>T
MANE Select: NM_001270
dbSNP: rs368819719
Type: single nucleotide variant
Location: chr5:98901300 (GRCh38)
Gene constraint: LOEUF 0.207 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.63 · 18 PDB
Residue 158: the 'disordered' region

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

Similar variants

CHD1 p.Ser158Pro 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
CHD1 p.Arg70Ter 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-ser158phe (accessed [today's date]).

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