Is EDRF1 p.Asp559Glu (c.1677T>G) pathogenic?

EDRF1 p.Asp559Glu (c.1677T>G) is classified Uncertain significance in EDRF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0827); Ultra-rare (popmax 0.0319%, sas).

How common is EDRF1 p.Asp559Glu (c.1677T>G) in the general population?

EDRF1 p.Asp559Glu (c.1677T>G) is ultra-rare (popmax 0.0319%, sas) (gnomAD).

What do computational predictors say about EDRF1 p.Asp559Glu (c.1677T>G)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

EDRF1 p.Asp559Glu

c.1677T>G · VCV4016254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0319%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.122	moderately benign-leaning
SaProt	LLR -5.57	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 -5.9	GERP -3.9
Regional constraint	o/e 0.77	unconstrained · MANE · 38 kb · p 3.4e-16 · regional, not allelic
Overall
CADD	0.809	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 0.0319% South Asian · 29/91,030 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.00186% 30/1,613,534 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0319%	3,139
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: EDRF1
Protein: p.Asp559Glu
Coding: c.1677T>G
MANE Select: NM_001202438
Type: single nucleotide variant
Location: chr10:125735823 (GRCh38)
Gene constraint: LOEUF 0.53 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 76.41
Residue 559: the 'disordered' region

Full EDRF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDRF1 p.Leu159= Benign ★★ same type
EDRF1 p.Thr480= Benign ★★ same type
EDRF1 p.Thr731= Benign ★★ same type
EDRF1 p.Ala1137Ser Uncertain significance ★ ⚠ same type
EDRF1 p.Ala1210Thr Uncertain significance ★ ⚠ same type
EDRF1 p.Ala1228Thr Uncertain significance ★ ⚠ same type
EDRF1 p.Ala203Thr Uncertain significance ★ ⚠ same type
EDRF1 p.Ala226Ser 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/edrf1-p-asp559glu (accessed [today's date]).

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