Is STRN4 p.Ser612Phe (c.1835C>T) pathogenic?

STRN4 p.Ser612Phe (c.1835C>T) is classified Uncertain significance in STRN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-10). AlphaMissense: ambiguous (0.3472); Very rare (popmax 0.00822%, nfe).

How common is STRN4 p.Ser612Phe (c.1835C>T) in the general population?

STRN4 p.Ser612Phe (c.1835C>T) is very rare (popmax 0.00822%, nfe) (gnomAD).

What do computational predictors say about STRN4 p.Ser612Phe (c.1835C>T)?

AlphaMissense predicts ambiguous (score 0.3472) — an in-silico prediction, not a clinical call.

STRN4 p.Ser612Phe

c.1835C>T · VCV3323441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00822%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3472	ambiguous
REVEL	0.592	indeterminate
SaProt	LLR -12.99	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 5,032 bp · p 9.4e-18 · regional, not allelic
Overall
CADD	25.8	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 0.00822% European (non-Finnish) · 97/1,180,048 alleles

Filtering AF 0.00689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00626% 101/1,614,030 alleles · very rare exomes 93/1,461,646 · genomes 8/152,384 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00822%	12,165
Remaining individualsnot grpmax-eligible	0.0032%	31,255
Finnishnot grpmax-eligible	0.00313%	31,903

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: STRN4
Protein: p.Ser612Phe
Coding: c.1835C>T
MANE Select: NM_013403
Type: single nucleotide variant
Location: chr19:46722881 (GRCh38)
Gene constraint: LOEUF 0.523 · pLI 0.85 (gnomAD)
Structure: AlphaFold pLDDT 68.59

Full STRN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FKRP c.-253+4A>G Uncertain significance ★★ same type
FKRP c.-253+5G>A Uncertain significance ★★ same type
STRN4 p.Pro158= Benign ★★ same type
FKRP c.-272G>A Conflicting classifications of pathogenicity ★ same type
STRN4 c.1154-14T>G Uncertain significance ★ same type
STRN4 c.1154-7T>C Uncertain significance ★ same type
STRN4 c.1907-1G>T Uncertain significance ★ same type
STRN4 c.737+1G>C 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/strn4-p-ser612phe (accessed [today's date]).

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