Is EEFSEC p.Arg583Pro (c.1748G>C) pathogenic?

EEFSEC p.Arg583Pro (c.1748G>C) is classified Uncertain significance in EEFSEC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-18). AlphaMissense: likely pathogenic (0.9907); Very rare (popmax 8.49e-05%, nfe).

How common is EEFSEC p.Arg583Pro (c.1748G>C) in the general population?

EEFSEC p.Arg583Pro (c.1748G>C) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about EEFSEC p.Arg583Pro (c.1748G>C)?

AlphaMissense predicts likely pathogenic (score 0.9907) — an in-silico prediction, not a clinical call.

EEFSEC p.Arg583Pro

c.1748G>C · rs372392092 · VCV2311040

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9907	likely pathogenic · top 7% in EEFSEC
REVEL	0.429	indeterminate
SaProt	LLR -16.84	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 9.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 255 kb · p 0.039 · regional, not allelic
Overall
CADD	27.5	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 8.49e-05% European (non-Finnish) · 1/1,178,196 alleles

Overall 0.000657% 1/152,210 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: EEFSEC
Protein: p.Arg583Pro
Coding: c.1748G>C
MANE Select: NM_021937
dbSNP: rs372392092
Type: single nucleotide variant
Location: chr3:128408216 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 583: a UniProt-annotated variant site (in nedpsb; likely pathogenic; decreased selenocysteine incorporation in selenoproteins); a β-strand

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

Similar variants

EEFSEC p.Arg285Gln Uncertain significance ★★ ⚠ same type
EEFSEC p.Arg424Gln Uncertain significance ★★ ⚠ same type
EEFSEC p.Phe463Leu Uncertain significance ★★ ⚠ same type
EEFSEC p.Ala435Val Benign ★★ same type
EEFSEC p.Phe581Cys Benign ★★ same type
EEFSEC p.Pro180= Benign ★★ same type
EEFSEC p.Asp390Ala Likely pathogenic ★ ⚠ same type
EEFSEC p.Glu514Ter Likely pathogenic ★ 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/eefsec-p-arg583pro (accessed [today's date]).

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