Is HUNK p.Pro414Ser (c.1240C>T) pathogenic?

HUNK p.Pro414Ser (c.1240C>T) is classified Uncertain significance in HUNK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). AlphaMissense: likely benign (0.0658); Very rare (popmax 0.000424%, nfe).

How common is HUNK p.Pro414Ser (c.1240C>T) in the general population?

HUNK p.Pro414Ser (c.1240C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about HUNK p.Pro414Ser (c.1240C>T)?

AlphaMissense predicts likely benign (score 0.0658) — an in-silico prediction, not a clinical call.

HUNK p.Pro414Ser

c.1240C>T · rs1384835488 · VCV3107622

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0658	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -5.02	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 -0.26	GERP -3.6
Regional constraint	o/e 0.93	unconstrained · MANE · 25 kb · p 0.14 · regional, not allelic
Overall
CADD	0.65	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,570 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,256 alleles · very rare exomes 5/1,461,036 · genomes 0/152,220 · 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: HUNK
Protein: p.Pro414Ser
Coding: c.1240C>T
MANE Select: NM_014586
dbSNP: rs1384835488
Type: single nucleotide variant
Location: chr21:31983592 (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-pro414ser (accessed [today's date]).

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