Is HLCS p.Val443Phe (c.1327G>T) pathogenic?

HLCS p.Val443Phe (c.1327G>T) is classified Uncertain significance in HLCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-25). AlphaMissense: likely benign (0.0902); Very rare (popmax 0.00439%, sas); Associated with Inborn genetic diseases.

What condition is associated with HLCS p.Val443Phe (c.1327G>T)?

HLCS p.Val443Phe (c.1327G>T) is associated with Inborn genetic diseases (ClinVar).

How common is HLCS p.Val443Phe (c.1327G>T) in the general population?

HLCS p.Val443Phe (c.1327G>T) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about HLCS p.Val443Phe (c.1327G>T)?

AlphaMissense predicts likely benign (score 0.0902) — an in-silico prediction, not a clinical call.

HLCS p.Val443Phe

c.1327G>T · VCV4621571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0902	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -8.22	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 -0.46	GERP -0.066
Regional constraint	o/e 0.90	unconstrained · MANE · 212 kb · p 0.00098 · regional, not allelic
Overall
CADD	5.656	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 V296F vs ClinVar V443F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,086 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000274% 4/1,461,880 alleles · very rare

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.Val443Phe
Coding: c.1327G>T
MANE Select: NM_001352514
Type: single nucleotide variant
Location: chr21:36936559 (GRCh38)
Gene constraint: LOEUF 0.883 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 77.33

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.Val443Gly Uncertain significance ★ ⚠ same residue
HLCS p.Val443Ile Uncertain significance ★ ⚠ same residue
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

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-val443phe (accessed [today's date]).

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