Is HPDL p.Val259= (c.777G>T) pathogenic?

HPDL p.Val259= (c.777G>T) is classified Likely benign in HPDL (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-01). Ultra-rare (popmax 0.0179%, amr).

How common is HPDL p.Val259= (c.777G>T) in the general population?

HPDL p.Val259= (c.777G>T) is ultra-rare (popmax 0.0179%, amr) (gnomAD).

HPDL p.Val259=

c.777G>T · VCV4872854

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.16	GERP -3.7, phastCons 0.75
Overall
CADD	1.096	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0179% Admixed American · 10/55,904 alleles

Filtering AF 0.00961% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.0104% 163/1,571,628 alleles · ultra-rare exomes 146/1,419,294 · genomes 17/152,334 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.163%	614
Remaining individualsnot grpmax-eligible	0.0231%	4,320
Admixed Americangrpmax	0.0179%	5,590
South Asian	0.00834%	11,990
European (non-Finnish)	0.0076%	13,154
African / African-American	0.00135%	73,946

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: HPDL
Protein: p.Val259=
Coding: c.777G>T
MANE Select: NM_032756
Type: single nucleotide variant
Location: chr1:45327925 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.45
Residue 259: a UniProt-annotated variant site (in nedswma); the voc 2 domain

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

Similar variants

HPDL p.Gln32Ter Pathogenic/Likely pathogenic ★★ same type
HPDL p.Gly50Asp Pathogenic ★★ ⚠ same type
HPDL p.Met1Ile Pathogenic/Likely pathogenic ★★ same type
HPDL p.Thr263Met Likely pathogenic ★★ ⚠ same type
HPDL p.Asn353Ile Uncertain significance ★★ ⚠ same type
HPDL p.Gly292Glu Uncertain significance ★★ ⚠ same type
HPDL c.*79G>A Benign ★★ same type
HPDL p.Glu339= Likely benign ★★ 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/hpdl-p-val259 (accessed [today's date]).

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