Is EEFSEC p.Met592Thr (c.1775T>C) pathogenic?

EEFSEC p.Met592Thr (c.1775T>C) is classified Uncertain significance in EEFSEC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.8813); Ultra-rare (popmax 0.0166%, mid).

How common is EEFSEC p.Met592Thr (c.1775T>C) in the general population?

EEFSEC p.Met592Thr (c.1775T>C) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about EEFSEC p.Met592Thr (c.1775T>C)?

AlphaMissense predicts likely pathogenic (score 0.8813) — an in-silico prediction, not a clinical call.

EEFSEC p.Met592Thr

c.1775T>C · rs142819202 · VCV2384344

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8813 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8813	likely pathogenic
REVEL	0.226	benign-leaning
SaProt	LLR -4.79	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 255 kb · p 0.039 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,034 alleles

Filtering AF 0.00713% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00664%

Overall 0.00632% 101/1,599,146 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,034
European (non-Finnish)	0.00853%	11,717

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.Met592Thr
Coding: c.1775T>C
MANE Select: NM_021937
dbSNP: rs142819202
Type: single nucleotide variant
Location: chr3:128408243 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.98 · 4 PDB
Residue 592: 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.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-met592thr (accessed [today's date]).

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