Is ENG p.Asp248fs (c.742_743insT) pathogenic?

ENG p.Asp248fs (c.742743insT) is classified Uncertain significance in ENG (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-09-16). Very rare (popmax 6.84e-05%).

How common is ENG p.Asp248fs (c.742_743insT) in the general population?

ENG p.Asp248fs (c.742_743insT) is very rare (popmax 6.84e-05%) (gnomAD).

ENG p.Asp248fs

c.742_743insT · rs1213847963 · VCV591252

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 6 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.1	GERP 0.51, phastCons 0.39
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,252 alleles · very rare

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: ENG
Protein: p.Asp248fs
Coding: c.742_743insT
MANE Select: NM_001114753
dbSNP: rs1213847963
Type: Insertion
Location: chr9:127825304 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 80.84 · 3 PDB
Residue 248: a disulfide bond; the 'required for interaction with gdf2' region; the 'or1, c-terminal part' region

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

Similar variants

ENG p.Asp248His Uncertain significance ★ ⚠ same residue
ENG p.Asp248Asn Benign ★ same residue
ENG p.Glu195fs Pathogenic ★★ same type
ENG p.Tyr455fs Pathogenic/Likely pathogenic ★★ same type
ENG p.Asp491fs Pathogenic ★ same type
ENG p.Gly74fs Pathogenic ★ same type
ENG p.Leu147fs Pathogenic ★ same type
ENG p.Val504fs 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/eng-p-asp248fs (accessed [today's date]).

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