Is SLC7A7 p.Pro421Gln (c.1262C>A) pathogenic?

SLC7A7 p.Pro421Gln (c.1262C>A) is classified Uncertain significance in SLC7A7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-20). AlphaMissense: likely pathogenic (0.9576); Very rare (popmax 8.47e-05%, nfe); Associated with lysinuric protein intolerance.

What condition is associated with SLC7A7 p.Pro421Gln (c.1262C>A)?

SLC7A7 p.Pro421Gln (c.1262C>A) is associated with lysinuric protein intolerance (ClinVar).

How common is SLC7A7 p.Pro421Gln (c.1262C>A) in the general population?

SLC7A7 p.Pro421Gln (c.1262C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Lysinuric protein intolerance inherited?

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

What do computational predictors say about SLC7A7 p.Pro421Gln (c.1262C>A)?

AlphaMissense predicts likely pathogenic (score 0.9576) — an in-silico prediction, not a clinical call.

SLC7A7 p.Pro421Gln

c.1262C>A · VCV3640976

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9576 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lysinuric protein intolerance

Computational evidence

Protein change
AlphaMissense	0.9576	likely pathogenic
REVEL	0.86	moderately pathogenic-leaning
SaProt	LLR -13.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.98	acceptor gain · deltas
Pangolin	Δ0.86	gain · loss 0.63 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 40 kb · p 0.08 · regional, not allelic
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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) · 1/1,180,022 alleles

Overall 6.2e-05% 1/1,614,098 alleles · very rare exomes 1/1,461,854 · genomes 0/152,244 · 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.Pro421Gln
Coding: c.1262C>A
MANE Select: NM_003982
Type: single nucleotide variant
Location: chr14:22774100 (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.Pro421= 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-pro421gln (accessed [today's date]).

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