Is SAE1 p.Ser86Phe (c.257C>T) pathogenic?

SAE1 p.Ser86Phe (c.257C>T) is classified Uncertain significance in SAE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-11). AlphaMissense: likely benign (0.1916); Very rare (popmax 0.00119%, nfe).

How common is SAE1 p.Ser86Phe (c.257C>T) in the general population?

SAE1 p.Ser86Phe (c.257C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about SAE1 p.Ser86Phe (c.257C>T)?

AlphaMissense predicts likely benign (score 0.1916) — an in-silico prediction, not a clinical call.

SAE1 p.Ser86Phe

c.257C>T · VCV3791764

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1916 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1916	likely benign
REVEL	0.31	indeterminate
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 3.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 78 kb · p 0.045 · regional, not allelic
Overall
CADD	23.6	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 0.00119% European (non-Finnish) · 14/1,179,782 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00347% 56/1,613,068 alleles · very rare exomes 52/1,460,980 · genomes 4/152,088 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.132%	759
Remaining individualsnot grpmax-eligible	0.00481%	20,803
European (non-Finnish)grpmax	0.00119%	84,270

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SAE1
Protein: p.Ser86Phe
Coding: c.257C>T
MANE Select: NM_005500
Type: single nucleotide variant
Location: chr19:47150248 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 91.78 · 14 PDB

Full SAE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SAE1 p.Tyr262= Benign ★★ same type
SAE1 p.Ala128Gly Uncertain significance ★ ⚠ same type
SAE1 p.Ala231Val Uncertain significance ★ ⚠ same type
SAE1 p.Arg235Cys Uncertain significance ★ ⚠ same type
SAE1 p.Arg35Trp Uncertain significance ★ ⚠ same type
SAE1 p.Arg38Gln Uncertain significance ★ ⚠ same type
SAE1 p.Arg83Cys Uncertain significance ★ ⚠ same type
SAE1 p.Arg89Gln 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/sae1-p-ser86phe (accessed [today's date]).

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