Is EEFSEC p.Phe463Leu (c.1389C>G) pathogenic?

EEFSEC p.Phe463Leu (c.1389C>G) is classified Uncertain significance in EEFSEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-17). AlphaMissense: likely benign (0.2482); Ultra-rare (popmax 0.0852%, afr).

How common is EEFSEC p.Phe463Leu (c.1389C>G) in the general population?

EEFSEC p.Phe463Leu (c.1389C>G) is ultra-rare (popmax 0.0852%, afr) (gnomAD).

What do computational predictors say about EEFSEC p.Phe463Leu (c.1389C>G)?

AlphaMissense predicts likely benign (score 0.2482) — an in-silico prediction, not a clinical call.

EEFSEC p.Phe463Leu

c.1389C>G · rs112227741 · VCV3087333

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2482 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0852%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2482	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -3.46	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 0.38	GERP -0.8, phastCons 0.002
Regional constraint	o/e 0.93	unconstrained · MANE · 255 kb · p 0.039 · regional, not allelic
Overall
CADD	6.54	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 0.0852% African / African-American · 64/75,074 alleles

Filtering AF 0.0685% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0624%

Overall 0.0057% 92/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0852%	1,173
Remaining individualsnot grpmax-eligible	0.0304%	3,290
Admixed American	0.015%	6,670

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.Phe463Leu
Coding: c.1389C>G
MANE Select: NM_021937
dbSNP: rs112227741
Type: single nucleotide variant
Location: chr3:128341835 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 463: a UniProt-annotated variant site (in nedpsb; likely pathogenic; decreased selenocysteine incorporation in selenoproteins)

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.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
EEFSEC p.Ala193Ser 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/eefsec-p-phe463leu (accessed [today's date]).

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