Is SLC7A7 p.Pro421= (c.1263G>C) pathogenic?

SLC7A7 p.Pro421= (c.1263G>C) is classified Uncertain significance in SLC7A7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). Very rare (popmax 0.0011%, sas); Associated with lysinuric protein intolerance.

What condition is associated with SLC7A7 p.Pro421= (c.1263G>C)?

SLC7A7 p.Pro421= (c.1263G>C) is associated with lysinuric protein intolerance (ClinVar).

How common is SLC7A7 p.Pro421= (c.1263G>C) in the general population?

SLC7A7 p.Pro421= (c.1263G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Lysinuric protein intolerance inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SLC7A7 p.Pro421=

c.1263G>C · rs1043886041 · VCV2010676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

lysinuric protein intolerance

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
REVEL	0.059	moderately benign-leaning
Splicing
SpliceAI	Δ0.27	acceptor loss · deltas
Pangolin	Δ0.30	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.4	GERP 0.9, phastCons 1
Overall
CADD	4.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,080 alleles

Overall 6.2e-05% 1/1,614,068 alleles · very rare exomes 1/1,461,866 · genomes 0/152,202 · joint denominator

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: SLC7A7
Protein: p.Pro421=
Coding: c.1263G>C
MANE Select: NM_003982
dbSNP: rs1043886041
Type: single nucleotide variant
Location: chr14:22774099 (GRCh38)
Gene constraint: LOEUF 1.007 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.89 · 6 PDB
Residue 421: an α-helix

Full SLC7A7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lysinuric protein intolerance — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lysinuric protein intolerance (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SLC7A7 p.Pro421Gln Uncertain significance ★ ⚠ same residue
SLC7A7 p.Pro421Leu Uncertain significance ★ ⚠ same residue
SLC7A7 p.Pro421fs Likely pathogenic same residue
SLC7A7 c.1429+1G>C Pathogenic ★★ same condition
SLC7A7 c.625+1G>A Pathogenic ★★ same condition
SLC7A7 c.625+1G>T Pathogenic/Likely pathogenic ★★ same condition
SLC7A7 c.770+1G>T Pathogenic/Likely pathogenic ★★ same condition
SLC7A7 c.894+1G>T 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/slc7a7-p-pro421 (accessed [today's date]).

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