Is RTN2 p.Pro310His (c.929C>A) pathogenic?

RTN2 p.Pro310His (c.929C>A) is classified Benign/Likely benign in RTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-27). AlphaMissense: likely benign (0.102); Rare (popmax 0.747%, afr); Associated with Spastic paraplegia.

What condition is associated with RTN2 p.Pro310His (c.929C>A)?

RTN2 p.Pro310His (c.929C>A) is associated with Spastic paraplegia (ClinVar).

How common is RTN2 p.Pro310His (c.929C>A) in the general population?

RTN2 p.Pro310His (c.929C>A) is rare (popmax 0.747%, afr) (gnomAD).

What do computational predictors say about RTN2 p.Pro310His (c.929C>A)?

AlphaMissense predicts likely benign (score 0.102) — an in-silico prediction, not a clinical call.

RTN2 p.Pro310His

c.929C>A · rs141012670 · VCV696212

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.102 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.747%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.102	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -7.35	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 8.1	GERP 2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	24.2	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 0.747% African / African-American · 560/75,004 alleles

Filtering AF 0.695% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.675%

Overall 0.0374% 603/1,613,582 alleles · rare exomes 300/1,461,242 · genomes 303/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.747%	134
Remaining individualsnot grpmax-eligible	0.0272%	3,674
Admixed American	0.0234%	4,269
European (non-Finnish)	0.00102%	98,324

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: RTN2
Protein: p.Pro310His
Coding: c.929C>A
MANE Select: NM_005619
dbSNP: rs141012670
Type: single nucleotide variant
Location: chr19:45493264 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 310: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic)

Full RTN2 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

RTN2 p.Pro310Ser Uncertain significance ★★ ⚠ same residue
RTN2 p.Glu50Ter Pathogenic/Likely pathogenic ★★ same condition
RTN2 c.1497+3G>A Uncertain significance ★★ same condition
RTN2 p.Ala529Thr Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg152Pro Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg252Trp Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg398Cys Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg447Gln Uncertain significance ★★ ⚠ 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/rtn2-p-pro310his (accessed [today's date]).

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