Is EEF1D p.Pro556Ala (c.1666C>G) pathogenic?

EEF1D p.Pro556Ala (c.1666C>G) is classified Uncertain significance in EEF1D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). AlphaMissense: likely benign (0.2898); Ultra-rare (popmax 0.0107%, afr).

How common is EEF1D p.Pro556Ala (c.1666C>G) in the general population?

EEF1D p.Pro556Ala (c.1666C>G) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about EEF1D p.Pro556Ala (c.1666C>G)?

AlphaMissense predicts likely benign (score 0.2898) — an in-silico prediction, not a clinical call.

EEF1D p.Pro556Ala

c.1666C>G · VCV3274547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2898 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2898	likely benign
REVEL	0.741	pathogenic-leaning
SaProt	LLR -10.65	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 10 kb · p 0.79 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P190A vs ClinVar P556A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,926 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000744% 12/1,613,000 alleles · ultra-rare exomes 9/1,460,770 · genomes 3/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,366
South Asian	0.0011%	91,052
European (non-Finnish)	0.000254%	393,290

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: EEF1D
Protein: p.Pro556Ala
Coding: c.1666C>G
MANE Select: NM_001130053
Type: single nucleotide variant
Location: chr8:143580550 (GRCh38)
Gene constraint: LOEUF 1.085 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 4 PDB
Residue 190 UniProt numbering: a turn; the 'catalytic (gef)' region

Full EEF1D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EEF1D c.1905+1G>A Uncertain significance ★★ same type
EEF1D p.Arg585Cys Uncertain significance ★★ ⚠ same type
EEF1D p.Asp100Gly Uncertain significance ★★ same type
EEF1D p.Asp386Asn Uncertain significance ★★ ⚠ same type
EEF1D p.Gly351Ala Uncertain significance ★★ same type
EEF1D p.Pro350Leu Uncertain significance ★★ same type
EEF1D p.Ser213Asn Uncertain significance ★★ same type
EEF1D p.Thr575Met 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/eef1d-p-pro556ala (accessed [today's date]).

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