Is HERC2 p.Pro406Arg (c.1217C>G) pathogenic?

HERC2 p.Pro406Arg (c.1217C>G) is classified Uncertain significance in HERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: ambiguous (0.407); Very rare (popmax 0.00017%, nfe); Associated with developmental delay with autism spectrum disorder and gait instability.

What condition is associated with HERC2 p.Pro406Arg (c.1217C>G)?

HERC2 p.Pro406Arg (c.1217C>G) is associated with developmental delay with autism spectrum disorder and gait instability (ClinVar).

How common is HERC2 p.Pro406Arg (c.1217C>G) in the general population?

HERC2 p.Pro406Arg (c.1217C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about HERC2 p.Pro406Arg (c.1217C>G)?

AlphaMissense predicts ambiguous (score 0.407) — an in-silico prediction, not a clinical call.

HERC2 p.Pro406Arg

Q: How is Developmental delay with autism spectrum disorder and gait instability inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1217C>G · VCV4883065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.407 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

developmental delay with autism spectrum disorder and gait instability

Computational evidence

Protein change
AlphaMissense	0.407	ambiguous
REVEL	0.628	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 31 kb · p 0.0039 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,856 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,906 alleles · very rare exomes 2/1,461,652 · genomes 0/152,254 · 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: HERC2
Protein: p.Pro406Arg
Coding: c.1217C>G
MANE Select: NM_004667
Type: single nucleotide variant
Location: chr15:28270735 (GRCh38)
Gene constraint: LOEUF 0.243 · pLI 1.00 (gnomAD)

Full HERC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental delay with autism spectrum disorder and gait instability — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Developmental delay with autism spectrum disorder and gait instability (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

HERC2 p.Arg1376Ter Pathogenic/Likely pathogenic ★★ same condition
HERC2 p.Ala200Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2582Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2671Gly Uncertain significance ★★ same condition
HERC2 p.Ala3439Thr Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala4253Thr Uncertain significance ★★ same condition
HERC2 p.Ala4345Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala876Val Uncertain significance ★★ ⚠ same condition

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/herc2-p-pro406arg (accessed [today's date]).

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