Is KANK4 p.Pro76Ser (c.226C>T) pathogenic?

KANK4 p.Pro76Ser (c.226C>T) is classified Uncertain significance in KANK4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: ambiguous (0.5224); Very rare (popmax 0.00666%, amr).

How common is KANK4 p.Pro76Ser (c.226C>T) in the general population?

KANK4 p.Pro76Ser (c.226C>T) is very rare (popmax 0.00666%, amr) (gnomAD).

What do computational predictors say about KANK4 p.Pro76Ser (c.226C>T)?

AlphaMissense predicts ambiguous (score 0.5224) — an in-silico prediction, not a clinical call.

KANK4 p.Pro76Ser

c.226C>T · VCV4680621

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5224 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5224	ambiguous
REVEL	0.172	moderately benign-leaning
SaProt	LLR -6.48	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 37 kb · p 0.46 · regional, not allelic
Overall
CADD	24.2	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 0.00666% Admixed American · 4/60,032 alleles

Filtering AF 0.00225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,614,180 alleles · very rare exomes 5/1,461,848 · genomes 0/152,332 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,008
European (non-Finnish)	8.47e-05%	1,179,997

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: KANK4
Protein: p.Pro76Ser
Coding: c.226C>T
MANE Select: NM_181712
Type: single nucleotide variant
Location: chr1:62274878 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.17
Residue 76: the 'disordered' region

Full KANK4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KANK4 p.Pro76Leu Uncertain significance ★ ⚠ same residue
KANK4 p.Pro76= Likely benign ★ same residue
KANK4 p.Ala115Val Uncertain significance ★★ ⚠ same type
KANK4 p.Ala987Thr Uncertain significance ★★ ⚠ same type
KANK4 p.Arg336Met Uncertain significance ★★ ⚠ same type
KANK4 p.Arg471Cys Uncertain significance ★★ ⚠ same type
KANK4 p.Arg653Cys Uncertain significance ★★ ⚠ same type
KANK4 p.Arg790Gln 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/kank4-p-pro76ser (accessed [today's date]).

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