Is HEXA p.Pro446Arg (c.1337C>G) pathogenic?

HEXA p.Pro446Arg (c.1337C>G) is classified Uncertain significance in HEXA (ClinVar, Single submitter, 1 submitter; last evaluated 2018-02-02). AlphaMissense: likely benign (0.0842); Absent from gnomAD v4.1.

How common is HEXA p.Pro446Arg (c.1337C>G) in the general population?

HEXA p.Pro446Arg (c.1337C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HEXA p.Pro446Arg (c.1337C>G)?

AlphaMissense predicts likely benign (score 0.0842) — an in-silico prediction, not a clinical call.

HEXA p.Pro446Arg

c.1337C>G · rs939203533 · VCV618678

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0842 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0842	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -9.89	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 2.9	GERP -1.8, phastCons 0.22
Regional constraint	o/e 0.99	unconstrained · MANE · 32 kb · p 0.87 · regional, not allelic
Overall
CADD	14.58	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HEXA
Protein: p.Pro446Arg
Coding: c.1337C>G
MANE Select: NM_000520
dbSNP: rs939203533
Type: single nucleotide variant
Location: chr15:72346319 (GRCh38)
Gene constraint: LOEUF 0.947 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.62 · 2 PDB
Residue 446: an α-helix

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

Similar variants

HEXA p.Pro446Leu Uncertain significance ★★ ⚠ same residue
HEXA p.Pro446Ser Uncertain significance ★ ⚠ same residue
HEXA p.Pro446= Likely benign ★ same residue
HEXA c.1073+1G>A Pathogenic/Likely pathogenic ★★ same type
HEXA c.1330+1G>A Pathogenic ★★ same type
HEXA c.1330+2T>C Pathogenic ★★ same type
HEXA c.1421+1G>C Pathogenic ★★ same type
HEXA c.1421+1G>T Pathogenic/Likely pathogenic ★★ 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/hexa-p-pro446arg (accessed [today's date]).

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