Is HLCS p.Ile703Val (c.2107A>G) pathogenic?

HLCS p.Ile703Val (c.2107A>G) is classified Uncertain significance in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-02). AlphaMissense: likely benign (0.0961); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with HLCS p.Ile703Val (c.2107A>G)?

HLCS p.Ile703Val (c.2107A>G) is associated with Inborn genetic diseases (ClinVar).

How common is HLCS p.Ile703Val (c.2107A>G) in the general population?

HLCS p.Ile703Val (c.2107A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about HLCS p.Ile703Val (c.2107A>G)?

AlphaMissense predicts likely benign (score 0.0961) — an in-silico prediction, not a clinical call.

HLCS p.Ile703Val

c.2107A>G · VCV4621565

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0961	likely benign
REVEL	0.283	benign-leaning
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -1.7, phastCons 0.001
Regional constraint	o/e 0.90	unconstrained · MANE · 212 kb · p 0.00098 · regional, not allelic
Overall
CADD	16.89	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 and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I556V vs ClinVar I703V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.19e-05% 1/1,614,234 alleles · very rare exomes 1/1,461,888 · genomes 0/152,346 · 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: HLCS
Protein: p.Ile703Val
Coding: c.2107A>G
MANE Select: NM_001352514
Type: single nucleotide variant
Location: chr21:36765026 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.33
Residue 556 UniProt numbering: the bpl/lpl catalytic domain

Full HLCS 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

HLCS p.Arg330Trp Uncertain significance ★★ ⚠ same condition
HLCS p.Arg627Cys Uncertain significance ★★ ⚠ same condition
HLCS p.Asn303Ile Uncertain significance ★★ ⚠ same condition
HLCS p.Asp318Asn Uncertain significance ★★ ⚠ same condition
HLCS p.Gln161Glu Uncertain significance ★★ ⚠ same condition
HLCS p.Gln386His Uncertain significance ★★ ⚠ same condition
HLCS p.Glu739Lys Uncertain significance ★★ ⚠ same condition
HLCS p.Glu850Lys 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/hlcs-p-ile703val (accessed [today's date]).

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