Is RTN4 p.Ser181Phe (c.542C>T) pathogenic?

RTN4 p.Ser181Phe (c.542C>T) is classified Uncertain significance in RTN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-31). AlphaMissense: likely benign (0.2413); Ultra-rare (popmax 0.0501%, mid).

How common is RTN4 p.Ser181Phe (c.542C>T) in the general population?

RTN4 p.Ser181Phe (c.542C>T) is ultra-rare (popmax 0.0501%, mid) (gnomAD).

What do computational predictors say about RTN4 p.Ser181Phe (c.542C>T)?

AlphaMissense predicts likely benign (score 0.2413) — an in-silico prediction, not a clinical call.

RTN4 p.Ser181Phe

c.542C>T · rs200934135 · VCV2411748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2413 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0501%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2413	likely benign
REVEL	0.113	moderately benign-leaning
SaProt	LLR -9.76	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 9.1	GERP 0.15, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 77 kb · p 3e-13 · regional, not allelic
Overall
CADD	23.8	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 0.0501% Middle Eastern · 2/3,996 alleles

Filtering AF 0.0143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0142% 190/1,342,372 alleles · ultra-rare exomes 170/1,190,302 · genomes 20/152,070 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0501%	1,998
Remaining individualsnot grpmax-eligible	0.0198%	5,049
European (non-Finnish)	0.0163%	6,123
African / African-American	0.00613%	16,306
Finnishnot grpmax-eligible	0.00463%	21,586
Admixed American	0.00371%	26,986

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.Ser181Phe
Coding: c.542C>T
MANE Select: NM_020532
dbSNP: rs200934135
Type: single nucleotide variant
Location: chr2:55049759 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 40.92 · 2 PDB
Residue 181: a modified residue (phosphoserine); the 'disordered' region

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-ser181phe (accessed [today's date]).

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