Is ANKS4B p.Phe205Ser (c.614T>C) pathogenic?

ANKS4B p.Phe205Ser (c.614T>C) is classified Uncertain significance in ANKS4B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-28). AlphaMissense: likely pathogenic (0.5869); Very rare (popmax 8.47e-05%, nfe).

How common is ANKS4B p.Phe205Ser (c.614T>C) in the general population?

ANKS4B p.Phe205Ser (c.614T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ANKS4B p.Phe205Ser (c.614T>C)?

AlphaMissense predicts likely pathogenic (score 0.5869) — an in-silico prediction, not a clinical call.

ANKS4B p.Phe205Ser

c.614T>C · VCV3874569

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5869 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5869	likely pathogenic
REVEL	0.115	moderately benign-leaning
SaProt	LLR -10.77	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 17 kb · p 0.33 · regional, not allelic
Overall
CADD	24.6	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 8.47e-05% European (non-Finnish) · 1/1,180,046 alleles

Overall 6.2e-05% 1/1,613,990 alleles · very rare exomes 0/1,461,892 · genomes 1/152,098 · 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: ANKS4B
Protein: p.Phe205Ser
Coding: c.614T>C
MANE Select: NM_145865
Type: single nucleotide variant
Location: chr16:21250180 (GRCh38)
Gene constraint: LOEUF 1.325 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.57
Residue 205: the 'mediates localization to microvilli' region

Full ANKS4B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKS4B p.Ala139Val Uncertain significance ★ ⚠ same type
ANKS4B p.Ala143Thr Uncertain significance ★ ⚠ same type
ANKS4B p.Ala40Asp Uncertain significance ★ ⚠ same type
ANKS4B p.Arg134Ser Uncertain significance ★ same type
ANKS4B p.Arg4His Uncertain significance ★ ⚠ same type
ANKS4B p.Asp245His Uncertain significance ★ ⚠ same type
ANKS4B p.Asp289Val Uncertain significance ★ ⚠ same type
ANKS4B p.Asp31His 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/anks4b-p-phe205ser (accessed [today's date]).

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