Is HERC2 p.Pro339Ser (c.1015C>T) pathogenic?

HERC2 p.Pro339Ser (c.1015C>T) is classified Likely benign in HERC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-01). AlphaMissense: likely benign (0.2812); No allele count reported in gnomAD v4.1 (AN 1,612,230); Associated with Inborn genetic diseases.

What condition is associated with HERC2 p.Pro339Ser (c.1015C>T)?

HERC2 p.Pro339Ser (c.1015C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HERC2 p.Pro339Ser (c.1015C>T) in the general population?

HERC2 p.Pro339Ser (c.1015C>T) is no allele count reported in gnomAD v4.1 (AN 1,612,230) (gnomAD).

What do computational predictors say about HERC2 p.Pro339Ser (c.1015C>T)?

AlphaMissense predicts likely benign (score 0.2812) — an in-silico prediction, not a clinical call.

HERC2 p.Pro339Ser

c.1015C>T · rs140932450 · VCV2342783

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2812 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,612,230)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2812	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; 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 9.9	phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 31 kb · p 0.0039 · regional, not allelic
Overall
CADD	22.4	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

No allele count reported in gnomAD v4.1 (AN 1,612,230). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: HERC2
Protein: p.Pro339Ser
Coding: c.1015C>T
MANE Select: NM_004667
dbSNP: rs140932450
Type: single nucleotide variant
Location: chr15:28272283 (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-pro339ser (accessed [today's date]).

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