Is KCNQ4 p.Ser320Phe (c.959C>T) pathogenic?

KCNQ4 p.Ser320Phe (c.959C>T) is classified Uncertain significance in KCNQ4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-10). AlphaMissense: likely pathogenic (0.9981); Absent from gnomAD v4.1.

How common is KCNQ4 p.Ser320Phe (c.959C>T) in the general population?

KCNQ4 p.Ser320Phe (c.959C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KCNQ4 p.Ser320Phe (c.959C>T)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

KCNQ4 p.Ser320Phe

c.959C>T · VCV3572701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic · top 5% in KCNQ4
REVEL	0.962	strongly pathogenic-leaning
SaProt	LLR -16.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.7, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 287 bp · p 1.1e-06 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KCNQ4
Protein: p.Ser320Phe
Coding: c.959C>T
MANE Select: NM_004700
Type: single nucleotide variant
Location: chr1:40820178 (GRCh38)
Gene constraint: LOEUF 0.602 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 66.37 · 13 PDB
Residue 320: an α-helix

Full KCNQ4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

KCNQ4 p.Ser320= Likely benign same residue
KCNQ4 p.Gly285Ser Pathogenic ★★★ same type
KCNQ4 p.Trp275Cys Likely pathogenic ★★★ same type
KCNQ4 p.Thr240= Likely benign ★★★ same type
KCNQ4 c.406-2A>G Likely pathogenic ★★ same type
KCNQ4 p.Gln122Ter Likely pathogenic ★★ same type
KCNQ4 p.Gln480Ter Pathogenic/Likely pathogenic ★★ same type
KCNQ4 p.Gly321Ser Pathogenic/Likely pathogenic ★★ 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/kcnq4-p-ser320phe (accessed [today's date]).

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