Is HSDL2 p.Pro154Arg (c.461C>G) pathogenic?

HSDL2 p.Pro154Arg (c.461C>G) is classified Uncertain significance in HSDL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely pathogenic (0.7624); Very rare (popmax 0.00205%, nfe).

How common is HSDL2 p.Pro154Arg (c.461C>G) in the general population?

HSDL2 p.Pro154Arg (c.461C>G) is very rare (popmax 0.00205%, nfe) (gnomAD).

What do computational predictors say about HSDL2 p.Pro154Arg (c.461C>G)?

AlphaMissense predicts likely pathogenic (score 0.7624) — an in-silico prediction, not a clinical call.

HSDL2 p.Pro154Arg

c.461C>G · rs199957858 · VCV3107191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00205%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7624	likely pathogenic
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -12.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	donor gain, 38 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 90 kb · p 0.021 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00205% European (non-Finnish) · 24/1,171,574 alleles

Filtering AF 0.00139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.0102% 164/1,604,354 alleles · very rare exomes 151/1,452,206 · genomes 13/152,148 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.437%	229
Remaining individualsnot grpmax-eligible	0.0161%	6,216
European (non-Finnish)grpmax	0.00205%	48,815
Admixed American	0.00167%	59,888

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: HSDL2
Protein: p.Pro154Arg
Coding: c.461C>G
MANE Select: NM_032303
dbSNP: rs199957858
Type: single nucleotide variant
Location: chr9:112416906 (GRCh38)
Gene constraint: LOEUF 1.174 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.91 · 1 PDB

Full HSDL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HSDL2 c.395+8T>C Benign ★★ same type
HSDL2 p.Lys298= Benign ★★ same type
HSDL2 p.Lys91Ile Benign ★★ same type
HSDL2 p.Ala146Val Uncertain significance ★ ⚠ same type
HSDL2 p.Ala194Pro Uncertain significance ★ ⚠ same type
HSDL2 p.Ala25Gly Uncertain significance ★ ⚠ same type
HSDL2 p.Ala84Thr Uncertain significance ★ ⚠ same type
HSDL2 p.Arg20His 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/hsdl2-p-pro154arg (accessed [today's date]).

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