Is EEFSEC p.Leu515Met (c.1543C>A) pathogenic?

EEFSEC p.Leu515Met (c.1543C>A) is classified Uncertain significance in EEFSEC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely benign (0.0812); Very rare (popmax 0.00169%, nfe).

How common is EEFSEC p.Leu515Met (c.1543C>A) in the general population?

EEFSEC p.Leu515Met (c.1543C>A) is very rare (popmax 0.00169%, nfe) (gnomAD).

What do computational predictors say about EEFSEC p.Leu515Met (c.1543C>A)?

AlphaMissense predicts likely benign (score 0.0812) — an in-silico prediction, not a clinical call.

EEFSEC p.Leu515Met

c.1543C>A · rs779354673 · VCV3087336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0812 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0812	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -5.79	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 0.55	GERP 0.33, phastCons 0.06
Regional constraint	o/e 0.93	unconstrained · MANE · 255 kb · p 0.039 · regional, not allelic
Overall
CADD	11.07	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 0.00169% European (non-Finnish) · 20/1,180,046 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00137% 20/1,461,880 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.Leu515Met
Coding: c.1543C>A
MANE Select: NM_021937
dbSNP: rs779354673
Type: single nucleotide variant
Location: chr3:128358316 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 515: 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.Leu515Pro Uncertain significance ★ ⚠ same residue
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

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-leu515met (accessed [today's date]).

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