Is SLC16A2 p.Arg297Pro (c.890G>C) pathogenic?

SLC16A2 p.Arg297Pro (c.890G>C) is classified Uncertain significance in SLC16A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-24). AlphaMissense: likely benign (0.0889); Very rare (popmax 0.000112%, nfe); Associated with Spastic paraplegia.

What condition is associated with SLC16A2 p.Arg297Pro (c.890G>C)?

SLC16A2 p.Arg297Pro (c.890G>C) is associated with Spastic paraplegia (ClinVar).

How common is SLC16A2 p.Arg297Pro (c.890G>C) in the general population?

SLC16A2 p.Arg297Pro (c.890G>C) is very rare (popmax 0.000112%, nfe) (gnomAD).

What do computational predictors say about SLC16A2 p.Arg297Pro (c.890G>C)?

AlphaMissense predicts likely benign (score 0.0889) — an in-silico prediction, not a clinical call.

SLC16A2 p.Arg297Pro

c.890G>C · rs780086745 · VCV1514289

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0889 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000112%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0889	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.53
Regional constraint	o/e 0.66	unconstrained · MANE · 6,945 bp · p 3.2e-07 · regional, not allelic
Overall
CADD	1.359	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000112% European (non-Finnish) · 1/895,437 alleles

Overall 0.000165% 2/1,211,618 alleles · very rare exomes 2/1,098,080 · genomes 0/113,538 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0021%	47,650
European (non-Finnish)grpmax	0.000112%	895,440

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SLC16A2
Protein: p.Arg297Pro
Coding: c.890G>C
MANE Select: NM_006517
dbSNP: rs780086745
Type: single nucleotide variant
Location: chrX:74524673 (GRCh38)
Structure: AlphaFold pLDDT 79.48 · 7 PDB

Full SLC16A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SLC16A2 p.Arg297His Conflicting classifications of pathogenicity ★ ⚠ same residue
SLC16A2 p.Arg297Ser Pathogenic ★ ⚠ same residue
SLC16A2 p.Arg297Leu Uncertain significance ★ ⚠ same residue
SLC16A2 c.1399+1G>A Pathogenic ★★ same condition
SLC16A2 c.576-1G>A Pathogenic/Likely pathogenic ★★ same condition
SLC16A2 p.Arg171Ter Pathogenic ★★ same condition
SLC16A2 p.Gln16Ter Pathogenic ★★ same condition
SLC16A2 p.Gln52Ter 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/slc16a2-p-arg297pro (accessed [today's date]).

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