Is ANKS6 p.Ser628Phe (c.1883C>T) pathogenic?

ANKS6 p.Ser628Phe (c.1883C>T) is classified Uncertain significance in ANKS6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-20). AlphaMissense: likely benign (0.2243); Rare (popmax 0.195%, sas); Associated with nephronophthisis 16.

What condition is associated with ANKS6 p.Ser628Phe (c.1883C>T)?

ANKS6 p.Ser628Phe (c.1883C>T) is associated with nephronophthisis 16 (ClinVar).

How common is ANKS6 p.Ser628Phe (c.1883C>T) in the general population?

ANKS6 p.Ser628Phe (c.1883C>T) is rare (popmax 0.195%, sas) (gnomAD).

How is Nephronophthisis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ANKS6 p.Ser628Phe (c.1883C>T)?

AlphaMissense predicts likely benign (score 0.2243) — an in-silico prediction, not a clinical call.

ANKS6 p.Ser628Phe

c.1883C>T · rs554990244 · VCV1385124

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2243 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.195%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephronophthisis 16

Computational evidence

Protein change
AlphaMissense	0.2243	likely benign
REVEL	0.268	benign-leaning
SaProt	LLR -9.01	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 9.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 60 kb · p 0.79 · regional, not allelic
Overall
CADD	26.1	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 0.195% South Asian · 172/88,040 alleles

Filtering AF 0.171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.162%

Overall 0.0117% 187/1,597,830 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.195%	512
Remaining individualsnot grpmax-eligible	0.021%	4,756
European (non-Finnish)	0.000171%	586,039

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: ANKS6
Protein: p.Ser628Phe
Coding: c.1883C>T
MANE Select: NM_173551
dbSNP: rs554990244
Type: single nucleotide variant
Location: chr9:98770985 (GRCh38)
Gene constraint: LOEUF 0.869 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.60 · 1 PDB
Residue 628: the 'disordered' region

Full ANKS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nephronophthisis 16 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Nephronophthisis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Finland)

Similar variants

ANKS6 c.1973-3C>G Pathogenic/Likely pathogenic ★★ same condition
ANKS6 p.Arg461Ter Pathogenic/Likely pathogenic ★★ same condition
ANKS6 c.907+6C>T Uncertain significance ★★ same condition
ANKS6 p.Ala215Thr Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala215Val Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala249Thr Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala261Thr Uncertain significance ★★ ⚠ same condition
ANKS6 p.Ala350Thr 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/anks6-p-ser628phe (accessed [today's date]).

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