Is CPS1 p.Asp1084His (c.3250G>C) pathogenic?

CPS1 p.Asp1084His (c.3250G>C) is classified Uncertain significance in CPS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-01). AlphaMissense: ambiguous (0.5504); Very rare (popmax 8.47e-05%, nfe).

How common is CPS1 p.Asp1084His (c.3250G>C) in the general population?

CPS1 p.Asp1084His (c.3250G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CPS1 p.Asp1084His (c.3250G>C)?

AlphaMissense predicts ambiguous (score 0.5504) — an in-silico prediction, not a clinical call.

CPS1 p.Asp1084His

c.3250G>C · rs777363145 · VCV871309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5504	ambiguous
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -7.45	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense 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 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	24.9	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 8.47e-05% European (non-Finnish) · 1/1,179,952 alleles

Overall 6.84e-05% 1/1,461,720 alleles · very 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: CPS1
Protein: p.Asp1084His
Coding: c.3250G>C
MANE Select: NM_001875
dbSNP: rs777363145
Type: single nucleotide variant
Location: chr2:210647971 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 1084: an α-helix

Full CPS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPS1 p.Asp1084Asn Uncertain significance ★★ ⚠ same residue
CPS1 c.1086+1G>A Likely pathogenic ★★ same type
CPS1 c.1087-1G>T Pathogenic/Likely pathogenic ★★ same type
CPS1 c.1165-2A>G Likely pathogenic ★★ same type
CPS1 c.1263+5G>C Pathogenic/Likely pathogenic ★★ same type
CPS1 c.1549+1G>A Pathogenic/Likely pathogenic ★★ same type
CPS1 c.1549+1G>T Pathogenic/Likely pathogenic ★★ same type
CPS1 c.1837-8A>G Pathogenic/Likely pathogenic ★★ 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/cps1-p-asp1084his (accessed [today's date]).

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