Is RTN4 p.Ser956Phe (c.2867C>T) pathogenic?

RTN4 p.Ser956Phe (c.2867C>T) is classified Uncertain significance in RTN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: likely benign (0.1297); Ultra-rare (popmax 0.0165%, mid).

How common is RTN4 p.Ser956Phe (c.2867C>T) in the general population?

RTN4 p.Ser956Phe (c.2867C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about RTN4 p.Ser956Phe (c.2867C>T)?

AlphaMissense predicts likely benign (score 0.1297) — an in-silico prediction, not a clinical call.

RTN4 p.Ser956Phe

c.2867C>T · VCV3436231

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1297 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1297	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -8.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 77 kb · p 3e-13 · regional, not allelic
Overall
CADD	24.7	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 0.0165% Middle Eastern · 1/6,058 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00155% 25/1,613,838 alleles · ultra-rare exomes 21/1,461,562 · genomes 4/152,276 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.0032%	31,249
European (non-Finnish)	0.00178%	56,182
South Asian	0.0011%	91,078

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: RTN4
Protein: p.Ser956Phe
Coding: c.2867C>T
MANE Select: NM_020532
Type: single nucleotide variant
Location: chr2:55025232 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 40.92 · 2 PDB

Full RTN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RTN4 p.Glu899Gln Benign ★★ same type
RTN4 p.Gly1070Ala Likely benign ★★ same type
RTN4 p.Leu620= Benign ★★ same type
RTN4 p.Leu814Met Likely benign ★★ same type
RTN4 p.Pro992= Benign ★★ same type
RTN4 p.Ser440Asn Benign ★★ same type
RTN4 p.Ser920Cys Benign ★★ same type
RTN4 p.Thr450Met Benign ★★ same type

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/rtn4-p-ser956phe (accessed [today's date]).

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