Is FADS2 p.Ile412Val (c.1234A>G) pathogenic?

FADS2 p.Ile412Val (c.1234A>G) is classified Uncertain significance in FADS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-17). AlphaMissense: likely benign (0.0767); Ultra-rare (popmax 0.0167%, mid).

How common is FADS2 p.Ile412Val (c.1234A>G) in the general population?

FADS2 p.Ile412Val (c.1234A>G) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about FADS2 p.Ile412Val (c.1234A>G)?

AlphaMissense predicts likely benign (score 0.0767) — an in-silico prediction, not a clinical call.

FADS2 p.Ile412Val

c.1234A>G · rs374653405 · VCV3091559

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0767 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0767	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -6.38	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 0.3	GERP 0.097, phastCons 0.22
Regional constraint	o/e 0.52	unconstrained · MANE · 25 kb · p 1.5e-23 · regional, not allelic
Overall
CADD	12.79	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 0.0167% Middle Eastern · 1/5,994 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.0013% 21/1,613,702 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,994
African / African-American	0.0147%	6,811
Remaining individualsnot grpmax-eligible	0.00961%	10,410
Admixed American	0.00167%	60,000
South Asian	0.0011%	91,088
European (non-Finnish)	8.47e-05%	1,180,004

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: FADS2
Protein: p.Ile412Val
Coding: c.1234A>G
MANE Select: NM_004265
dbSNP: rs374653405
Type: single nucleotide variant
Location: chr11:61865228 (GRCh38)
Gene constraint: LOEUF 0.415 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 95.39

Full FADS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FADS2 p.His221= Benign ★★ same type
FADS2 p.Ala115Val Uncertain significance ★ ⚠ same type
FADS2 p.Ala408Ser Uncertain significance ★ ⚠ same type
FADS2 p.Arg14Cys Uncertain significance ★ ⚠ same type
FADS2 p.Arg353His Uncertain significance ★ ⚠ same type
FADS2 p.Arg58Gln Uncertain significance ★ ⚠ same type
FADS2 p.Arg73Cys Uncertain significance ★ ⚠ same type
FADS2 p.Asn156His 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/fads2-p-ile412val (accessed [today's date]).

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