Is HERC2 p.Arg343Ser (c.1029G>T) pathogenic?

HERC2 p.Arg343Ser (c.1029G>T) is classified Uncertain significance in HERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: likely pathogenic (0.9853); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with HERC2 p.Arg343Ser (c.1029G>T)?

HERC2 p.Arg343Ser (c.1029G>T) is associated with Inborn genetic diseases (ClinVar).

How common is HERC2 p.Arg343Ser (c.1029G>T) in the general population?

HERC2 p.Arg343Ser (c.1029G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HERC2 p.Arg343Ser (c.1029G>T)?

AlphaMissense predicts likely pathogenic (score 0.9853) — an in-silico prediction, not a clinical call.

HERC2 p.Arg343Ser

c.1029G>T · rs758452157 · VCV2455015

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9853 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9853	likely pathogenic
REVEL	0.563	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6
Regional constraint	o/e 0.88	unconstrained · MANE · 31 kb · p 0.0039 · regional, not allelic
Overall
CADD	6.065	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

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: HERC2
Protein: p.Arg343Ser
Coding: c.1029G>T
MANE Select: NM_004667
dbSNP: rs758452157
Type: single nucleotide variant
Location: chr15:28272269 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HERC2 p.Ala1253Thr Uncertain significance ★★ same condition
HERC2 p.Ala1454Thr Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala200Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2331Val Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2458Thr Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala2671Gly Uncertain significance ★★ same condition
HERC2 p.Ala2948Ser Uncertain significance ★★ ⚠ same condition
HERC2 p.Ala3095Ser 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-arg343ser (accessed [today's date]).

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