Is SQLE p.Ser83Phe (c.248C>T) pathogenic?

SQLE p.Ser83Phe (c.248C>T) is classified Uncertain significance in SQLE (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: likely benign (0.0984); Very rare (popmax 0.00673%, afr).

How common is SQLE p.Ser83Phe (c.248C>T) in the general population?

SQLE p.Ser83Phe (c.248C>T) is very rare (popmax 0.00673%, afr) (gnomAD).

What do computational predictors say about SQLE p.Ser83Phe (c.248C>T)?

AlphaMissense predicts likely benign (score 0.0984) — an in-silico prediction, not a clinical call.

SQLE p.Ser83Phe

c.248C>T · VCV3449178

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00673%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0984	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -8.49	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 3.2	GERP 1.2, phastCons 0.082
Regional constraint	o/e 0.88	unconstrained · MANE · 23 kb · p 0.0025 · regional, not allelic
Overall
CADD	19.12	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 0.00673% African / African-American · 5/74,330 alleles

Filtering AF 0.00257% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00163%

Overall 0.000749% 12/1,602,402 alleles · very rare exomes 7/1,450,372 · genomes 5/152,030 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00673%	14,866
Remaining individualsnot grpmax-eligible	0.00161%	61,992
European (non-Finnish)	0.000511%	195,703

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: SQLE
Protein: p.Ser83Phe
Coding: c.248C>T
MANE Select: NM_003129
Type: single nucleotide variant
Location: chr8:124999651 (GRCh38)
Gene constraint: LOEUF 0.629 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 85.78 · 3 PDB
Residue 83: the 'interaction with marchf6' region

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

Similar variants

SQLE p.Ala24Ser Uncertain significance ★ ⚠ same type
SQLE p.Ala490Gly Uncertain significance ★ ⚠ same type
SQLE p.Ala552Thr Uncertain significance ★ ⚠ same type
SQLE p.Ala81Thr Uncertain significance ★ ⚠ same type
SQLE p.Arg228Gly Uncertain significance ★ ⚠ same type
SQLE p.Arg234Trp Uncertain significance ★ same type
SQLE p.Arg26Gly Uncertain significance ★ ⚠ same type
SQLE p.Arg401Gly 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/sqle-p-ser83phe (accessed [today's date]).

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