Is CPS1 p.Val41Phe (c.121G>T) pathogenic?

CPS1 p.Val41Phe (c.121G>T) is classified Conflicting classifications of pathogenicity in CPS1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.1344); Ultra-rare (popmax 0.0508%, afr); Associated with Inborn genetic diseases.

What condition is associated with CPS1 p.Val41Phe (c.121G>T)?

CPS1 p.Val41Phe (c.121G>T) is associated with Inborn genetic diseases, carbamoyl phosphate synthetase I deficiency disease (ClinVar).

How common is CPS1 p.Val41Phe (c.121G>T) in the general population?

CPS1 p.Val41Phe (c.121G>T) is ultra-rare (popmax 0.0508%, afr) (gnomAD).

What do computational predictors say about CPS1 p.Val41Phe (c.121G>T)?

AlphaMissense predicts likely benign (score 0.1344) — an in-silico prediction, not a clinical call.

CPS1 p.Val41Phe

c.121G>T · rs148708735 · VCV648563

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1344 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0508%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1344	likely benign
REVEL	0.51	indeterminate
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 0.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 121 kb · p 0.0019 · regional, not allelic
Overall
CADD	18.02	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 0.0508% African / African-American · 38/74,836 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0335%

Overall 0.00248% 40/1,612,790 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0508%	1,969
Remaining individualsnot grpmax-eligible	0.0032%	31,213

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.Val41Phe
Coding: c.121G>T
MANE Select: NM_001875
dbSNP: rs148708735
Type: single nucleotide variant
Location: chr2:210556854 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.80 · 14 PDB
Residue 41: the 'anthranilate phosphoribosyltransferase homolog' region

Full CPS1 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

Also linked: carbamoyl phosphate synthetase I deficiency disease

Similar variants

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
CPS1 c.1549+1G>T Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1837-8A>G Pathogenic/Likely pathogenic ★★ same condition
CPS1 c.1981+1G>C 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-val41phe (accessed [today's date]).

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