Is HEPHL1 p.Pro2fs (c.5del) pathogenic?

HEPHL1 p.Pro2fs (c.5del) is classified Likely pathogenic in HEPHL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). Ultra-rare (popmax 0.0542%, sas); Associated with pili torti-developmental delay-neurological abnormalities syndrome.

What condition is associated with HEPHL1 p.Pro2fs (c.5del)?

HEPHL1 p.Pro2fs (c.5del) is associated with pili torti-developmental delay-neurological abnormalities syndrome (ClinVar).

How common is HEPHL1 p.Pro2fs (c.5del) in the general population?

HEPHL1 p.Pro2fs (c.5del) is ultra-rare (popmax 0.0542%, sas) (gnomAD).

HEPHL1 p.Pro2fs

c.5del · VCV4850227

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0542%, sas)

Conditions

pili torti-developmental delay-neurological abnormalities syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 20
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	32.0	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 0.0542% South Asian · 49/90,470 alleles

Filtering AF 0.042% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0378%

Overall 0.00317% 51/1,610,880 alleles · ultra-rare exomes 43/1,458,582 · genomes 8/152,298 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0542%	1,846
Remaining individualsnot grpmax-eligible	0.00321%	31,171

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: HEPHL1
Protein: p.Pro2fs
Coding: c.5del
MANE Select: NM_001098672
Type: Deletion
Location: chr11:94021372 (GRCh38)
Gene constraint: LOEUF 1.145 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.76

Full HEPHL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pili torti-developmental delay-neurological abnormalities syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HEPHL1 c.1232+9C>G Benign ★★ same condition
HEPHL1 c.3046-35G>T Benign ★★ same condition
HEPHL1 p.Asn251Asp Benign ★★ same condition
HEPHL1 c.2906-1G>C Likely pathogenic ★ same condition
HEPHL1 p.Ser137Ter Likely pathogenic ★ same condition
HEPHL1 p.Tyr215Ter Likely pathogenic ★ same condition
HEPHL1 p.Asn880Ser Uncertain significance ★ ⚠ same condition
HEPHL1 p.Asp1017Gly Uncertain significance ★ ⚠ same condition

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/hephl1-p-pro2fs (accessed [today's date]).

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