Is SSTR4 p.Phe216Ser (c.647T>C) pathogenic?

SSTR4 p.Phe216Ser (c.647T>C) is classified Uncertain significance in SSTR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: ambiguous (0.4539); Very rare (popmax 0.00167%, amr).

How common is SSTR4 p.Phe216Ser (c.647T>C) in the general population?

SSTR4 p.Phe216Ser (c.647T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SSTR4 p.Phe216Ser (c.647T>C)?

AlphaMissense predicts ambiguous (score 0.4539) — an in-silico prediction, not a clinical call.

SSTR4 p.Phe216Ser

c.647T>C · VCV3449891

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4539 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
AlphaMissense	0.4539	ambiguous
REVEL	0.342	indeterminate
SaProt	LLR -8.01	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 0.82, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 1,163 bp · p 3.1e-06 · regional, not allelic
Overall
CADD	19.33	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 0.00167% Admixed American · 1/59,992 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000311% 5/1,605,522 alleles · very rare exomes 4/1,453,338 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,992
Remaining individualsnot grpmax-eligible	0.0016%	62,412
African / African-American	0.00133%	74,924
European (non-Finnish)	0.00017%	589,894

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: SSTR4
Protein: p.Phe216Ser
Coding: c.647T>C
MANE Select: NM_001052
Type: single nucleotide variant
Location: chr20:23036130 (GRCh38)
Structure: AlphaFold pLDDT 78.72 · 2 PDB
Residue 216: an α-helix

Full SSTR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SSTR4 p.Leu233= Benign ★★ same type
SSTR4 p.Thr17= Benign ★★ same type
SSTR4 p.Val210= Benign ★★ same type
SSTR4 p.Ala155Val Uncertain significance ★ ⚠ same type
SSTR4 p.Ala18Thr Uncertain significance ★ ⚠ same type
SSTR4 p.Ala240Val Uncertain significance ★ ⚠ same type
SSTR4 p.Ala28Ser Uncertain significance ★ ⚠ same type
SSTR4 p.Ala302Gly 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/sstr4-p-phe216ser (accessed [today's date]).

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