Is HMGA2 p.Pro48Arg (c.143C>G) pathogenic?

HMGA2 p.Pro48Arg (c.143C>G) is classified Uncertain significance in HMGA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-08-06). AlphaMissense: likely pathogenic (0.9341); Very rare (popmax 0.0011%, sas); Associated with Monogenic short statue.

What condition is associated with HMGA2 p.Pro48Arg (c.143C>G)?

HMGA2 p.Pro48Arg (c.143C>G) is associated with Monogenic short statue (ClinVar).

How common is HMGA2 p.Pro48Arg (c.143C>G) in the general population?

HMGA2 p.Pro48Arg (c.143C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about HMGA2 p.Pro48Arg (c.143C>G)?

AlphaMissense predicts likely pathogenic (score 0.9341) — an in-silico prediction, not a clinical call.

HMGA2 p.Pro48Arg

c.143C>G · VCV4880347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9341 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Monogenic short statue

Computational evidence

Protein change
AlphaMissense	0.9341	likely pathogenic
REVEL	0.362	indeterminate
SaProt	LLR -14.35	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 138 kb · p 0.019 · regional, not allelic
Overall
CADD	29.4	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 0.0011% South Asian · 1/91,066 alleles

Overall 0.000992% 16/1,613,658 alleles · very rare exomes 12/1,461,652 · genomes 4/152,006 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0187%	5,334
Remaining individualsnot grpmax-eligible	0.0032%	31,240
South Asiangrpmax	0.0011%	91,066
European (non-Finnish)	8.48e-05%	1,179,805

Finnish 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: HMGA2
Protein: p.Pro48Arg
Coding: c.143C>G
MANE Select: NM_003483
Type: single nucleotide variant
Location: chr12:65828032 (GRCh38)
Gene constraint: LOEUF 1.688 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 65.46
Residue 48: a DNA-binding region; the 'disordered' region; the 'interaction with e4f1' region

Full HMGA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Monogenic short statue

Similar variants

HMGA2 c.250-36248T>C Benign same condition
HMGA2 c.282+1012T>C Benign same condition
HMGA2 c.*1G>A Likely benign same condition
HMGA2 p.Gly5= Likely benign same condition
HMGA2 p.Glu42fs Likely pathogenic ★ same condition
HMGA2 c.199-8A>G Benign/Likely benign ★★ same type
HMGA2 p.Pro92Ala Likely benign ★★ same type
HMGA2 p.Ser105= 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/hmga2-p-pro48arg (accessed [today's date]).

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