Is CPS1 p.Pro1105Ser (c.3313C>T) pathogenic?

CPS1 p.Pro1105Ser (c.3313C>T) is classified Conflicting classifications of pathogenicity in CPS1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-18). AlphaMissense: likely benign (0.2324); Ultra-rare (popmax 0.0991%, mid); Associated with CPS1-related disorder.

What condition is associated with CPS1 p.Pro1105Ser (c.3313C>T)?

CPS1 p.Pro1105Ser (c.3313C>T) is associated with CPS1-related disorder, carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Pro1105Ser (c.3313C>T) in the general population?

CPS1 p.Pro1105Ser (c.3313C>T) is ultra-rare (popmax 0.0991%, mid) (gnomAD).

What do computational predictors say about CPS1 p.Pro1105Ser (c.3313C>T)?

AlphaMissense predicts likely benign (score 0.2324) — an in-silico prediction, not a clinical call.

CPS1 p.Pro1105Ser

c.3313C>T · rs761921978 · VCV897722

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2324 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0991%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CPS1-related disorder

Computational evidence

Protein change
AlphaMissense	0.2324	likely benign
REVEL	0.494	indeterminate
SaProt	LLR -11.40	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	22.4	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 0.0991% Middle Eastern · 6/6,054 alleles

Filtering AF 0.0613% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0561%

Overall 0.00527% 85/1,613,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0991%	1,009
South Asian	0.0758%	1,320
Remaining individualsnot grpmax-eligible	0.0064%	15,625
European (non-Finnish)	0.000509%	196,649

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.Pro1105Ser
Coding: c.3313C>T
MANE Select: NM_001875
dbSNP: rs761921978
Type: single nucleotide variant
Location: chr2:210648034 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 1105: the atp-grasp 2 domain

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

Disease context

CPS1-related disorder

Also linked: carbamoyl phosphate synthetase I deficiency disease

Similar variants

CPS1 p.Pro1105_Trp1106insTer Likely pathogenic ★ same residue
CPS1 p.Pro1105Arg Uncertain significance ★ same residue
CPS1 p.Pro1105Leu Uncertain significance ★ ⚠ same residue
CPS1 c.1086+1G>A Likely pathogenic ★★ same condition
CPS1 c.1087-1G>T Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1165-2A>G Likely pathogenic ★★ same condition
CPS1 c.1263+5G>C Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1549+1G>A Pathogenic/Likely pathogenic ★★ 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/cps1-p-pro1105ser (accessed [today's date]).

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