Is HERC2 p.Ser96Pro (c.286T>C) pathogenic?

HERC2 p.Ser96Pro (c.286T>C) is classified Uncertain significance in HERC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.1239); Ultra-rare (popmax 0.0226%, mid); Associated with Inborn genetic diseases.

What condition is associated with HERC2 p.Ser96Pro (c.286T>C)?

HERC2 p.Ser96Pro (c.286T>C) is associated with Inborn genetic diseases (ClinVar).

How common is HERC2 p.Ser96Pro (c.286T>C) in the general population?

HERC2 p.Ser96Pro (c.286T>C) is ultra-rare (popmax 0.0226%, mid) (gnomAD).

What do computational predictors say about HERC2 p.Ser96Pro (c.286T>C)?

AlphaMissense predicts likely benign (score 0.1239) — an in-silico prediction, not a clinical call.

HERC2 p.Ser96Pro

c.286T>C · VCV3525180

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1239 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0226%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1239	likely benign
REVEL	0.18	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 1.3	phastCons 0.1
Regional constraint	o/e 0.88	unconstrained · MANE · 31 kb · p 0.0039 · regional, not allelic
Overall
CADD	14.45	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0226% Middle Eastern · 1/4,428 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000497% 8/1,611,134 alleles · ultra-rare exomes 8/1,458,850 · genomes 0/152,284 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0226%	4,428
European (non-Finnish)	0.000593%	168,529

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.Ser96Pro
Coding: c.286T>C
MANE Select: NM_004667
Type: single nucleotide variant
Location: chr15:28292924 (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.Ser96Ala Uncertain significance ★★ ⚠ same residue
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

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-ser96pro (accessed [today's date]).

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