Is CHD8 p.Ser2083Phe (c.6248C>T) pathogenic?

CHD8 p.Ser2083Phe (c.6248C>T) is classified Conflicting classifications of pathogenicity in CHD8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.2415); Ultra-rare (popmax 0.0238%, amr); Associated with Inborn genetic diseases.

What condition is associated with CHD8 p.Ser2083Phe (c.6248C>T)?

CHD8 p.Ser2083Phe (c.6248C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHD8 p.Ser2083Phe (c.6248C>T) in the general population?

CHD8 p.Ser2083Phe (c.6248C>T) is ultra-rare (popmax 0.0238%, amr) (gnomAD).

What do computational predictors say about CHD8 p.Ser2083Phe (c.6248C>T)?

AlphaMissense predicts likely benign (score 0.2415) — an in-silico prediction, not a clinical call.

CHD8 p.Ser2083Phe

c.6248C>T · rs545239905 · VCV1307636

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2415 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0238%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2415	likely benign
REVEL	0.248	benign-leaning
SaProt	LLR -11.27	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 2,499 bp · p 8e-07 · regional, not allelic
Overall
CADD	25.0	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 0.0238% Admixed American · 14/58,904 alleles

Filtering AF 0.0143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.000871% 14/1,608,058 alleles · ultra-rare

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: CHD8
Protein: p.Ser2083Phe
Coding: c.6248C>T
MANE Select: NM_001170629
dbSNP: rs545239905
Type: single nucleotide variant
Location: chr14:21393547 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.17 · 2 PDB
Residue 2083: the 'interaction with fam124b' region; the 'disordered' region

Full CHD8 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

Similar variants

CHD8 c.3882+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHD8 p.Arg1462Ter Pathogenic ★★ same condition
CHD8 p.Arg1582Ter Pathogenic/Likely pathogenic ★★ same condition
CHD8 p.Arg2217Ter Pathogenic ★★ same condition
CHD8 p.Arg243Ter Pathogenic ★★ same condition
CHD8 c.4921+4C>T Uncertain significance ★★ same condition
CHD8 c.-1G>A Uncertain significance ★★ same condition
CHD8 p.Ala1960Thr 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/chd8-p-ser2083phe (accessed [today's date]).

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