Is HUNK p.Phe562Val (c.1684T>G) pathogenic?

HUNK p.Phe562Val (c.1684T>G) is classified Uncertain significance in HUNK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: ambiguous (0.4935); Ultra-rare (popmax 0.0117%, amr).

How common is HUNK p.Phe562Val (c.1684T>G) in the general population?

HUNK p.Phe562Val (c.1684T>G) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about HUNK p.Phe562Val (c.1684T>G)?

AlphaMissense predicts ambiguous (score 0.4935) — an in-silico prediction, not a clinical call.

HUNK p.Phe562Val

c.1684T>G · VCV4272997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4935 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Computational evidence

Protein change
AlphaMissense	0.4935	ambiguous
REVEL	0.472	indeterminate
SaProt	LLR -5.58	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 25 kb · p 0.14 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,010 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000682% 11/1,614,044 alleles · ultra-rare exomes 10/1,461,890 · genomes 1/152,154 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,573
Ashkenazi Jewishnot grpmax-eligible	0.00675%	14,804
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)	8.47e-05%	1,180,038

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: HUNK
Protein: p.Phe562Val
Coding: c.1684T>G
MANE Select: NM_014586
Type: single nucleotide variant
Location: chr21:31998723 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.83

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

Similar variants

HUNK p.Ala272Ser Uncertain significance ★ ⚠ same type
HUNK p.Ala4Val Uncertain significance ★ ⚠ same type
HUNK p.Ala590Asp Uncertain significance ★ ⚠ same type
HUNK p.Ala698Gly Uncertain significance ★ ⚠ same type
HUNK p.Arg119His Uncertain significance ★ ⚠ same type
HUNK p.Arg157Trp Uncertain significance ★ same type
HUNK p.Arg164His Uncertain significance ★ ⚠ same type
HUNK p.Arg179Trp 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/hunk-p-phe562val (accessed [today's date]).

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