Is HERC1 p.Arg2322Pro (c.6965G>C) pathogenic?

HERC1 p.Arg2322Pro (c.6965G>C) is classified Uncertain significance in HERC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-17). AlphaMissense: likely pathogenic (0.762); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HERC1 p.Arg2322Pro (c.6965G>C)?

HERC1 p.Arg2322Pro (c.6965G>C) is associated with Inborn genetic diseases (ClinVar).

How common is HERC1 p.Arg2322Pro (c.6965G>C) in the general population?

HERC1 p.Arg2322Pro (c.6965G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about HERC1 p.Arg2322Pro (c.6965G>C)?

AlphaMissense predicts likely pathogenic (score 0.762) — an in-silico prediction, not a clinical call.

HERC1 p.Arg2322Pro

c.6965G>C · rs374367917 · VCV2465532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.762 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.762	likely pathogenic
REVEL	0.228	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 41 kb · p 1.8e-08 · regional, not allelic
Overall
CADD	25.2	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 0.000424% European (non-Finnish) · 5/1,179,890 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,613,860 alleles · very rare exomes 5/1,461,698 · genomes 1/152,162 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,016
European (non-Finnish)grpmax	0.000424%	235,978

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: HERC1
Protein: p.Arg2322Pro
Coding: c.6965G>C
MANE Select: NM_003922
dbSNP: rs374367917
Type: single nucleotide variant
Location: chr15:63677950 (GRCh38)
Gene constraint: LOEUF 0.33 · pLI 1.00 (gnomAD)

Full HERC1 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

HERC1 p.Ala1494Val Uncertain significance ★★ ⚠ same condition
HERC1 p.Ala2289Thr Uncertain significance ★★ ⚠ same condition
HERC1 p.Ala276Glu Uncertain significance ★★ same condition
HERC1 p.Ala2875Val Uncertain significance ★★ ⚠ same condition
HERC1 p.Ala3045Val Uncertain significance ★★ ⚠ same condition
HERC1 p.Ala3598Thr Uncertain significance ★★ ⚠ same condition
HERC1 p.Ala4182Val Uncertain significance ★★ ⚠ same condition
HERC1 p.Arg1298His 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/herc1-p-arg2322pro (accessed [today's date]).

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