Is HERC1 p.Arg1663Ile (c.4988G>T) pathogenic?

HERC1 p.Arg1663Ile (c.4988G>T) is classified Uncertain significance in HERC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: likely benign (0.1514); Absent from gnomAD v4.1.

How common is HERC1 p.Arg1663Ile (c.4988G>T) in the general population?

HERC1 p.Arg1663Ile (c.4988G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HERC1 p.Arg1663Ile (c.4988G>T)?

AlphaMissense predicts likely benign (score 0.1514) — an in-silico prediction, not a clinical call.

HERC1 p.Arg1663Ile

c.4988G>T · rs1216703772 · VCV2499868

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1514 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1514	likely benign
REVEL	0.122	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 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 43 kb · p 0.00049 · regional, not allelic
Overall
CADD	22.2	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

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: HERC1
Protein: p.Arg1663Ile
Coding: c.4988G>T
MANE Select: NM_003922
dbSNP: rs1216703772
Type: single nucleotide variant
Location: chr15:63696257 (GRCh38)
Gene constraint: LOEUF 0.33 · pLI 1.00 (gnomAD)

Full HERC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HERC1 p.Arg2196Ter Pathogenic/Likely pathogenic ★★ same type
HERC1 p.Arg3248Ter Pathogenic/Likely pathogenic ★★ same type
HERC1 c.1026+6T>C Uncertain significance ★★ same type
HERC1 c.12570+6G>A Uncertain significance ★★ same type
HERC1 p.Ala1494Val Uncertain significance ★★ ⚠ same type
HERC1 p.Ala2289Thr Uncertain significance ★★ ⚠ same type
HERC1 p.Ala2539Thr Uncertain significance ★★ ⚠ same type
HERC1 p.Ala276Glu Uncertain significance ★★ same type

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-arg1663ile (accessed [today's date]).

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