Is EIF2D p.Ser299Phe (c.896C>T) pathogenic?

EIF2D p.Ser299Phe (c.896C>T) is classified Uncertain significance in EIF2D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-31). AlphaMissense: likely benign (0.1281); Very rare (popmax 0.00364%, nfe).

How common is EIF2D p.Ser299Phe (c.896C>T) in the general population?

EIF2D p.Ser299Phe (c.896C>T) is very rare (popmax 0.00364%, nfe) (gnomAD).

What do computational predictors say about EIF2D p.Ser299Phe (c.896C>T)?

AlphaMissense predicts likely benign (score 0.1281) — an in-silico prediction, not a clinical call.

EIF2D p.Ser299Phe

c.896C>T · VCV3274973

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1281 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00364%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1281	likely benign
REVEL	0.381	indeterminate
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 21 kb · p 6.2e-07 · regional, not allelic
Overall
CADD	32.0	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 0.00364% European (non-Finnish) · 43/1,179,854 alleles

Filtering AF 0.00275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00244%

Overall 0.00279% 45/1,613,892 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00364%	27,438
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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: EIF2D
Protein: p.Ser299Phe
Coding: c.896C>T
MANE Select: NM_006893
Type: single nucleotide variant
Location: chr1:206602342 (GRCh38)
Gene constraint: LOEUF 0.862 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.23 · 3 PDB

Full EIF2D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EIF2D p.Ala149Ser Uncertain significance ★ ⚠ same type
EIF2D p.Ala150Val Uncertain significance ★ ⚠ same type
EIF2D p.Ala24Thr Uncertain significance ★ ⚠ same type
EIF2D p.Ala499Val Uncertain significance ★ ⚠ same type
EIF2D p.Arg20Ser Uncertain significance ★ ⚠ same type
EIF2D p.Arg508Gln Uncertain significance ★ ⚠ same type
EIF2D p.Arg527Gln Uncertain significance ★ ⚠ same type
EIF2D p.Arg7Trp 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/eif2d-p-ser299phe (accessed [today's date]).

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