Is HDGF p.Val140Phe (c.418G>T) pathogenic?

HDGF p.Val140Phe (c.418G>T) is classified Uncertain significance in HDGF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-17). AlphaMissense: likely pathogenic (0.6118); Ultra-rare (popmax 0.0286%, nfe).

How common is HDGF p.Val140Phe (c.418G>T) in the general population?

HDGF p.Val140Phe (c.418G>T) is ultra-rare (popmax 0.0286%, nfe) (gnomAD).

What do computational predictors say about HDGF p.Val140Phe (c.418G>T)?

AlphaMissense predicts likely pathogenic (score 0.6118) — an in-silico prediction, not a clinical call.

HDGF p.Val140Phe

c.418G>T · rs143813161 · VCV2396518

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6118 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0286%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6118	likely pathogenic
REVEL	0.152	moderately benign-leaning
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 1,648 bp · p 0.014 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0286% European (non-Finnish) · 338/1,180,042 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0251%

Overall 0.0224% 361/1,614,022 alleles · ultra-rare exomes 341/1,461,882 · genomes 20/152,140 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.032%	3,124
European (non-Finnish)grpmax	0.0286%	3,491
African / African-American	0.00267%	37,446
Admixed American	0.00167%	60,000

Remaining individuals 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: HDGF
Protein: p.Val140Phe
Coding: c.418G>T
MANE Select: NM_004494
dbSNP: rs143813161
Type: single nucleotide variant
Location: chr1:156744234 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.83 · 2 PDB
Residue 140: the 'disordered' region

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

Similar variants

HDGF p.Val140Ile Uncertain significance ★ ⚠ same residue
HDGF p.Ala153Gly Uncertain significance ★ ⚠ same type
HDGF p.Ala153Val Uncertain significance ★ ⚠ same type
HDGF p.Arg208Gln Uncertain significance ★ ⚠ same type
HDGF p.Arg208Gly Uncertain significance ★ ⚠ same type
HDGF p.Arg208Trp Uncertain significance ★ ⚠ same type
HDGF p.Asn174Tyr Uncertain significance ★ ⚠ same type
HDGF p.Asn43Lys 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/hdgf-p-val140phe (accessed [today's date]).

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