Is HDGF p.Ser103Phe (c.308C>T) pathogenic?

HDGF p.Ser103Phe (c.308C>T) is classified Uncertain significance in HDGF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-08). AlphaMissense: likely benign (0.152); Very rare (popmax 0.000424%, nfe).

How common is HDGF p.Ser103Phe (c.308C>T) in the general population?

HDGF p.Ser103Phe (c.308C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about HDGF p.Ser103Phe (c.308C>T)?

AlphaMissense predicts likely benign (score 0.152) — an in-silico prediction, not a clinical call.

HDGF p.Ser103Phe

c.308C>T · VCV4675219

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.152 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.152	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -9.68	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 1,648 bp · p 0.014 · regional, not allelic
Overall
CADD	24.0	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 0.000424% European (non-Finnish) · 5/1,180,008 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,814 alleles · very rare exomes 3/1,461,714 · genomes 2/152,100 · joint denominator

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.Ser103Phe
Coding: c.308C>T
MANE Select: NM_004494
Type: single nucleotide variant
Location: chr1:156744344 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.83 · 2 PDB
Residue 103: the 'disordered' region

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

Similar variants

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
HDGF p.Asp164Asn 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-ser103phe (accessed [today's date]).

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