Is RPSA p.Ser138Phe (c.413C>T) pathogenic?

RPSA p.Ser138Phe (c.413C>T) is classified Uncertain significance in RPSA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely pathogenic (0.9958); Very rare (popmax 0.00401%, afr).

How common is RPSA p.Ser138Phe (c.413C>T) in the general population?

RPSA p.Ser138Phe (c.413C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about RPSA p.Ser138Phe (c.413C>T)?

AlphaMissense predicts likely pathogenic (score 0.9958) — an in-silico prediction, not a clinical call.

RPSA p.Ser138Phe

c.413C>T · rs1387989945 · VCV2060226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9958	likely pathogenic
REVEL	0.486	indeterminate
SaProt	LLR -14.06	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 2.4, phastCons 1
Regional constraint	o/e 0.18	constrained · MANE · 2,225 bp · p 4.2e-14 · regional, not allelic
Overall
CADD	25.7	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 0.00401% African / African-American · 3/74,758 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00197% 3/152,220 alleles · very rare

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: RPSA
Protein: p.Ser138Phe
Coding: c.413C>T
MANE Select: NM_002295
dbSNP: rs1387989945
Type: single nucleotide variant
Location: chr3:39410914 (GRCh38)
Gene constraint: LOEUF 0.144 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.45 · 204 PDB
Residue 138: a turn

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

Similar variants

RPSA p.Arg191Cys Uncertain significance ★★ ⚠ same type
RPSA p.Ile145Val Uncertain significance ★★ ⚠ same type
RPSA c.134-14C>T Likely benign ★★ same type
RPSA c.134-32C>T Benign ★★ same type
RPSA c.252+17T>C Benign/Likely benign ★★ same type
RPSA c.627+10T>C Likely benign ★★ same type
RPSA c.628-17T>C Likely benign ★★ same type
RPSA c.-8T>C Benign/Likely 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/rpsa-p-ser138phe (accessed [today's date]).

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