Is HERC2 p.Ile97Phe (c.289A>T) pathogenic?

HERC2 p.Ile97Phe (c.289A>T) is classified Uncertain significance in HERC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-01). AlphaMissense: likely benign (0.1483); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with HERC2 p.Ile97Phe (c.289A>T)?

HERC2 p.Ile97Phe (c.289A>T) is associated with Inborn genetic diseases (ClinVar).

How common is HERC2 p.Ile97Phe (c.289A>T) in the general population?

HERC2 p.Ile97Phe (c.289A>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about HERC2 p.Ile97Phe (c.289A>T)?

AlphaMissense predicts likely benign (score 0.1483) — an in-silico prediction, not a clinical call.

HERC2 p.Ile97Phe

c.289A>T · VCV3857563

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1483 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1483	likely benign
REVEL	0.202	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 2.4	phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 31 kb · p 0.0039 · regional, not allelic
Overall
CADD	21.2	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 0.00267% African / African-American · 2/74,926 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,611,088 alleles · very rare exomes 2/1,458,784 · genomes 0/152,304 · 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.Ile97Phe
Coding: c.289A>T
MANE Select: NM_004667
Type: single nucleotide variant
Location: chr15:28292921 (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-ile97phe (accessed [today's date]).

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