Is KANK4 p.Pro625Leu (c.1874C>T) pathogenic?

KANK4 p.Pro625Leu (c.1874C>T) is classified Uncertain significance in KANK4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-19). AlphaMissense: likely benign (0.0738); Ultra-rare (popmax 0.0111%, afr); Associated with KANK4-related disorder.

What condition is associated with KANK4 p.Pro625Leu (c.1874C>T)?

KANK4 p.Pro625Leu (c.1874C>T) is associated with KANK4-related disorder (ClinVar).

How common is KANK4 p.Pro625Leu (c.1874C>T) in the general population?

KANK4 p.Pro625Leu (c.1874C>T) is ultra-rare (popmax 0.0111%, afr) (gnomAD).

What do computational predictors say about KANK4 p.Pro625Leu (c.1874C>T)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

KANK4 p.Pro625Leu

c.1874C>T · rs760690246 · VCV2209307

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

KANK4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -7.26	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 8.8	GERP 0.03, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 37 kb · p 0.46 · regional, not allelic
Overall
CADD	22.0	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 0.0111% African / African-American · 8/71,820 alleles

Filtering AF 0.00548% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.00165% 25/1,516,744 alleles · ultra-rare exomes 19/1,364,566 · genomes 6/152,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0111%	8,977
South Asian	0.00531%	18,823
East Asian	0.00228%	43,772
Admixed American	0.00222%	45,028
European (non-Finnish)	0.000971%	102,954

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.Pro625Leu
Coding: c.1874C>T
MANE Select: NM_181712
dbSNP: rs760690246
Type: single nucleotide variant
Location: chr1:62273230 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.17
Residue 625: the 'disordered' region

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

Disease context

KANK4-related disorder

Similar variants

KANK4 p.Pro625= Likely benign ★ same residue
KANK4 p.Arg471Cys Uncertain significance ★★ ⚠ same condition
KANK4 p.Asp692Asn Uncertain significance ★★ ⚠ same condition
KANK4 p.Met977Lys Uncertain significance ★★ ⚠ same condition
KANK4 p.Arg122Gly Conflicting classifications of pathogenicity ★ ⚠ same condition
KANK4 p.His420Arg Uncertain significance ★ ⚠ same condition
KANK4 p.Leu182Gln Uncertain significance ★ ⚠ same condition
KANK4 p.His447Arg 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/kank4-p-pro625leu (accessed [today's date]).

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