Is AFDN p.Ile438Val (c.1312A>G) pathogenic?

AFDN p.Ile438Val (c.1312A>G) is classified Uncertain significance in AFDN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2015-03-25). AlphaMissense: likely benign (0.2567); Low-frequency (popmax 3.14%, mid).

How common is AFDN p.Ile438Val (c.1312A>G) in the general population?

AFDN p.Ile438Val (c.1312A>G) is low-frequency (popmax 3.14%, mid) (gnomAD).

What do computational predictors say about AFDN p.Ile438Val (c.1312A>G)?

AlphaMissense predicts likely benign (score 0.2567) — an in-silico prediction, not a clinical call.

AFDN p.Ile438Val

c.1312A>G · rs35140809 · VCV218493

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2567 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.14%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2567	likely benign
REVEL	0.52	indeterminate
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 51 kb · p 1.7e-06 · regional, not allelic
Overall
CADD	24.1	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 3.14% Middle Eastern · 190/6,042 alleles

Filtering AF 2.78% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.7%

Overall 2.41% 38,523/1,600,696 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	3.14%	32
European (non-Finnish)	2.73%	37
Finnishnot grpmax-eligible	2.58%	39
Remaining individualsnot grpmax-eligible	2.55%	39
Ashkenazi Jewishnot grpmax-eligible	2.53%	39
South Asian	1.42%	70
Admixed American	1.37%	73
African / African-American	0.425%	235
Amishnot grpmax-eligible	0.219%	456
East Asian	0.00446%	22,406

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: AFDN
Protein: p.Ile438Val
Coding: c.1312A>G
MANE Select: NM_001386888
dbSNP: rs35140809
Type: single nucleotide variant
Location: chr6:167896967 (GRCh38)
Gene constraint: LOEUF 0.398 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.69 · 6 PDB
Residue 438: the fha domain

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

Similar variants

AFDN c.4968+1G>C Uncertain significance ★ same type
AFDN p.Arg1634Leu Uncertain significance ★ ⚠ same type
AFDN p.Arg1717Ter Uncertain significance ★ same type
AFDN p.Arg999His Uncertain significance ★ ⚠ same type
AFDN p.Asp1176Glu Uncertain significance ★ ⚠ same type
AFDN p.Asp1516Ala Uncertain significance ★ ⚠ same type
AFDN p.Asp539His Uncertain significance ★ ⚠ same type
AFDN p.Gln1217Ter 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/afdn-p-ile438val (accessed [today's date]).

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