Is RER1 p.Phe146Leu (c.438C>G) pathogenic?

RER1 p.Phe146Leu (c.438C>G) is classified Uncertain significance in RER1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-22). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1.

How common is RER1 p.Phe146Leu (c.438C>G) in the general population?

RER1 p.Phe146Leu (c.438C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RER1 p.Phe146Leu (c.438C>G)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

RER1 p.Phe146Leu

c.438C>G · rs1344215226 · VCV3153008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 2% in RER1
REVEL	0.621	indeterminate
SaProt	LLR -14.22	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1.4, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 7,330 bp · p 3.6e-09 · regional, not allelic
Overall
CADD	25.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RER1
Protein: p.Phe146Leu
Coding: c.438C>G
MANE Select: NM_007033
dbSNP: rs1344215226
Type: single nucleotide variant
Location: chr1:2402279 (GRCh38)
Gene constraint: LOEUF 0.635 · pLI 0.81 (gnomAD)
Structure: AlphaFold pLDDT 79.25

Full RER1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PEX10 c.*420G>A Uncertain significance ★★ same type
RER1 p.Ala195Thr Uncertain significance ★ ⚠ same type
RER1 p.Gly191Ser Uncertain significance ★ ⚠ same type
RER1 p.Ile149Met Uncertain significance ★ ⚠ same type
RER1 p.Met156Leu Uncertain significance ★ ⚠ same type
RER1 p.Met92Lys Uncertain significance ★ ⚠ same type
RER1 p.Met92Val Uncertain significance ★ ⚠ same type
RER1 p.Pro144Leu Uncertain significance ★ ⚠ 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/rer1-p-phe146leu (accessed [today's date]).

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