Is HUNK p.Ala4Val (c.11C>T) pathogenic?

HUNK p.Ala4Val (c.11C>T) is classified Uncertain significance in HUNK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.9596); Very rare (popmax 0.00335%, nfe).

How common is HUNK p.Ala4Val (c.11C>T) in the general population?

HUNK p.Ala4Val (c.11C>T) is very rare (popmax 0.00335%, nfe) (gnomAD).

What do computational predictors say about HUNK p.Ala4Val (c.11C>T)?

AlphaMissense predicts likely pathogenic (score 0.9596) — an in-silico prediction, not a clinical call.

HUNK p.Ala4Val

c.11C>T · rs1193279874 · VCV3107621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00335%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9596	likely pathogenic
REVEL	0.13	moderately benign-leaning
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.77, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 101 kb · p 2.1e-10 · regional, not allelic
Overall
CADD	23.1	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 0.00335% European (non-Finnish) · 29/866,056 alleles

Filtering AF 0.00235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00203%

Overall 0.00289% 30/1,039,810 alleles · very rare exomes 29/891,736 · genomes 1/148,074 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00335%	29,864
Remaining individualsnot grpmax-eligible	0.00304%	32,924

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.Ala4Val
Coding: c.11C>T
MANE Select: NM_014586
dbSNP: rs1193279874
Type: single nucleotide variant
Location: chr21:31873685 (GRCh38)
Gene constraint: LOEUF 0.39 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.83
Residue 4: the 'disordered' region

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.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
HUNK p.Arg298His 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-ala4val (accessed [today's date]).

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